Acid/Base Equilibria

Acid-base definitions

I. Two definitions
A. Bronsted Lowry definition → transfer of protons (proton is a H+)
1. Bronsted Lowry (BL) Acid – proton donor
2. Bronsted Lowry (BL) Base – proton acceptor
3. Ex. Water and HCl … water is BL base, HCl is BL Acid
a. Cl- is conjugate base to HCl
b. H3O+ is conjugate acid to water

B. Lewis definition → transfer of electron pairs

1. Lewis acid – electron pair acceptor
2. Lewis base – electron pair donor
3. Ex. Water and BF3 … water is a Lewis Base, BF3 is a Lewis acid
a. Boron in this case does not have octet (it only has 6 electrons around it) and thus
it is sp2 hybridized, meaning that it has an empty orbital. This empty orbital can
accept an electron pair.
Since there is no H+ exchange here, this rx can only be explained by Lewis definition, not BL
definition.

If we were to classify the players in the first reaction (the H2O HCl example), then H2O would be
there Lewis base (since it is the electron pair donor), and the H+ on the HCl would be the Lewis
acid (since it is the electron pair acceptor). HCl is just a source of a Lewis acid here.

Ka and acid strength

I. H2O + HA ⇌ H30+ + A- Once this rx reaches equilibrium, we can write an equilibrium expression
A. Water is BL base
B. HA is BL Acid
C. Hydronium is conjugate acid
D. A– is conjugate base
II. Ka: acid dissociation/ionization constant
𝒑𝒓𝒐𝒅𝒖𝒄𝒕𝒔 [𝐻3 𝑂 + ][𝐴− ]
A. 𝑲𝒂 = 𝒓𝒆𝒂𝒄𝒕𝒂𝒏𝒕𝒔 = [𝐻𝐴]
Pure solids and liquids are not included in the equilibrium constant expression

III. Strong acids

Strong acids donate protons very easily, making the equilibrium shift to the right towards
products (i.e. almost all reactants turn into products)

The stronger the acid, the weaker the conjugate base (e.g. since the strong acid HCl is so good at
donating protons, the conjugate base Cl– must be rather poor at accepting them)
Large numerator over a small denominator makes Ka large.

This makes Ka very large for strong acids. Ka >>> 1

Large Ka is a good way to recognize a strong acid.

IV. Weak acids have Ka values that are much smaller than 1.

Weak acids are more likely to ‘stay protonated’, (i.e. are less likely to donate their proton), and
thus reactant concentrations are likely to stay relatively high, and equilibrium is to the left
(towards the reactants)

Small numerator over a large denominator makes Ka small.

This makes Ka very small for weak acids. Ka <<< 1

Small Ka is a good way to recognize a weak acid.

Autoionization of water

I. Water is amphotetic, meaning that it can act as both an acid or as a base.

II. When two water molecules are near each other, one will act as a base and the other will act
as an acid (i.e. one will take a proton off of the other), producing a hydronium ion (H3O+) and
a hydroxide ion (OH–)

III. The Ka of this phenomenon is called Kw, the autoionization constant

𝒑𝒓𝒐𝒅𝒖𝒄𝒕𝒔 [𝐻3 𝑂+ ][𝐴− ]
Recall: 𝑲𝒂 = 𝒓𝒆𝒂𝒄𝒕𝒂𝒏𝒕𝒔 = [𝐻𝐴]
and you don’t write liquids (e.g. H2O) or solids, so in this situation…

𝑲𝒂 = 𝑲𝒘 = [𝑯𝟑 𝑶+ ][𝑶𝑯− ]

At 25°C, 𝐾𝑤 = (1.0 𝑥 10−7 )(1.0 𝑥 10−7 ) = 1.0 𝑥 10−14

[H3O+] and [OH–] values are just values that were previously were determined experimentally.

Since this equilibrium constant is much less than 1, equilibrium lies far to the left.

IV. Concentration of hydronium vs hydroxide

A. If [𝑯𝟑 𝑶+ ] = [𝑶𝑯− ], the solution is neutral
B. If [𝑯𝟑 𝑶+ ] > [𝑶𝑯− ], the solution is acidic
C. If [𝑯𝟑 𝑶+ ] < [𝑶𝑯− ], the solution is basic
V. Ex. If we have lemon juice with [𝐻3 𝑂+ ] = 2.2𝑥10−3 𝑀, what is the [𝑂𝐻 − ], and what kind of
solution is it?
A. [𝐻3 𝑂+ ][𝑂𝐻 − ] = 1.0 𝑥 10−4
(2.2 𝑥 10−3 𝑀)𝑥 = 1.0 𝑥 10−14 𝑀
𝑥 = 4.5 𝑥 10−12 𝑀
 B. Because the hydronium (H3O+) concentration is greater than the hydroxide (OH-)
concentration, the solution is acidic

Definition of pH

I. 𝑝𝐻 = − log[𝐻3 𝑂+ ] rearranges to [H3O+] = 10–pH

A. Example: pH of water at 25°C
1. 𝑝𝐻 = − log(1.0 𝑥 10−7 ) = 7.00
II. pH scale
A. pH = 7 → neutral
B. pH <7 → acidic
C. pH > 7 → basic
III. Example: Calculate hydronium ion concentration from pH
A. 3.82 = − log[𝐻3 𝑂+ ]
−3.82 = log[𝐻3 𝑂+ ]
[𝐻3 𝑂+ ] = 10−3.82 = 1.5 𝑥 10−4

IV. 𝑝𝑂𝐻 = −log [𝑂𝐻 − ]

A. Example: pOH of water at 25°C
1. 𝑝𝑂𝐻 = − log[𝑂𝐻 − ] = − log(1.0 𝑥 10−7 ) = 7.00

V. pH + pOH = 14

VI. Example: Calculate the pH of an aqueous ammonia solution with a [-OH] of 2.1 𝑥 10−3 𝑀
A. [𝐻3 𝑂+ ][𝑂𝐻 − ] = 1.0 𝑥 10−14
𝑥(2.1 𝑥 10−3 𝑀) = 1.0 𝑥 10−14 𝑀
𝑥 = [𝐻3 𝑂+ ] = 4.8 𝑥 10−12 𝑀
𝑝𝐻 = − log[𝐻3 𝑂+ ] = − log(4.8𝑥10−12 𝑀) = 11.32

B. 𝑝𝑂𝐻 = − log(2.1 𝑥 10−3 𝑀) = 2.68

𝑝𝐻 + 𝑝𝑂𝐻 = 14
𝑝𝐻 = 14 − 𝑝𝑂𝐻 = 14 − 2.68 = 11.32

(A) and (B) are just different ways to reach the same answer.
 ///

On the MCAT, calculators aren’t allowed. Use the following tricks to reach an answer in the right
ball park, and pick the MC answer that is closest to your estimate:

• If you see a number that looks like 1.0 x 10 x (e.g. 1.0 x 10-4 as an example), the pH is
simply the exponent without the negative sign (e.g. pH 4 in our example).
• If the first number isn't 1.0 (e.g. 2.4 x 10-6), there is a trick:
o The exponent is 6, but that is NOT your pH.
o The rule is that you subtract 0.5 from the exponent when you have a number other
than 1.0 before the x 10x
o So in our example of 2.4 x 10-6, we calculate 6 - 0.5 to be 5.5.
o The pH will be somewhere between 5.5 and 6.0
o Check the MC choices on the MCAT to see what answer falls within that range.
o This works because the MCAT will NOT have answers looking like 5.5, 5.7, 5.8, etc.
They will be more wide spread than that (2.0, 4.3, 5.7, 8.0, etc.)

///

Strong acids and strong bases

I. Strong acids ionize 100% in solution (ionization is the process by which an atom or a
molecule acquires a negative or positive charge by gaining or losing electrons to form ions)
(i.e. all reactants turn into products)
II.
A. Examples of strong acids: 𝐻𝐶𝑙𝑂4 , 𝐻𝑋 (𝑋 = 𝐶𝑙, 𝐵𝑟, 𝐼 ), 𝐻2 𝑆𝑂4 , 𝐻𝑁𝑂3

B. Example: Calculate pH of a 0.0030M 𝐻𝑁𝑂3 Solution

1. 𝐻𝑁𝑂3 + 𝐻2 𝑂 → 𝐻3 𝑂+ + 𝑁𝑂3−
2. In this case, the nitric acid ionizes 100% into hydronium so
a. 𝑝𝐻 = − log[𝐻3 𝑂+ ] = − log(0.030𝑀) = 1.52

III. Strong bases also ionize 100% in solution

A. Examples of strong bases: 𝑁𝑎𝑂𝐻, 𝐾𝑂𝐻, 𝐶𝑎(𝑂𝐻)2 , 𝑀𝑔(𝑂𝐻)2 (+ all metal hydroxides)

B. Example: Calculate pH of a 0.20M solution of NaOH

1. Because NaOH is a strong base, it will ionize fully into hydroxide
2. 𝑁𝑎𝑂𝐻 → 𝑁𝑎+ + 𝑂𝐻 −
3. [𝐻3 𝑂+ ][𝑂𝐻 − ] = 1.0 𝑥 10−14
[𝐻3 𝑂+ ](0.20𝑀 ) = 1.0 𝑥 10−14 𝑀
[𝐻3 𝑂+ ] = 5.0 𝑥 10−14 𝑀
𝑝𝐻 = − log[𝐻3 𝑂+ ] = − log(5.0𝑥10−14 𝑀) = 13.30
 4. 𝑝𝑂𝐻 = − log(0.20𝑀 ) = 0.70
𝑝𝐻 + 𝑝𝑂𝐻 = 14
𝑝𝐻 = 14 − 𝑝𝑂𝐻 = 14 − 0.70 = 13.30
(3. and 4. are just two different ways to get the same answer)

C. Example: Calculate the pH of an aqueous solution that contains 0.11g of 𝐶𝑎(𝑂𝐻)2 in a

total volume of 250ml
1. 𝐶𝑎(𝑂𝐻)2 → 𝐶𝑎2 + 2 𝑂𝐻 − (make sure to balance)
0.11𝑔
2. 𝑚𝑜𝑙𝑒𝑠 𝑜𝑓 𝐶𝑎(𝑂𝐻)2 = 𝑔 = 0.0015 𝑚𝑜𝑙 (finding moles of Ca(OH)2)
74( )
𝑚𝑜𝑙
a. This means we have 0.0030 𝑚𝑜𝑙 𝑜𝑓 𝑂𝐻 − (because of the ratio of 2 to 1)
0.0030 𝑚𝑜𝑙
b. [𝑂𝐻− ] = = 0.012 𝑀 (M is a concentration, measured in mol/L)
0.250 𝐿
3. [𝐻3 𝑂+ ][𝑂𝐻 − ] = 1.0 𝑥 10−14
[𝐻3 𝑂+ ](0.012𝑀) = 1.0 𝑥 10−14 𝑀
[𝐻3 𝑂+ ] = 8.3 𝑥 10−13 𝑀
𝑝𝐻 = − log[𝐻3 𝑂+ ] = − log(8.3𝑥10−13 𝑀) = 12.08
4. Alternatively to step 3, you could have found pOH = –log(0.012) and then done 14
minus pOH from 14 to find pH = 12.08.

Weak acid equilibrium

𝒑𝒓𝒐𝒅𝒖𝒄𝒕𝒔 [𝐻3 𝑂 + ][𝐴− ]

I. 𝑲𝒂 = 𝒓𝒆𝒂𝒄𝒕𝒂𝒏𝒕𝒔 = (recall: exclude pure liquids and pure solids)
[𝐻𝐴]
A. pKa = −𝐥𝐨𝐠 (𝑲𝒂)
B. Weak acids only partially dissociate in solution
C. Ka and pKa values of weak acids

Ka pKa
HF Hydrofluoric acid 3.5 𝑥 10 −4
3.46
𝐶𝐻3 𝐶𝑂𝑂𝐻 Acetic acid 1.8 𝑥 10 −5 4
𝐶𝐻3 𝑂𝐻 Methanol 2.9 𝑥 10 −16
15.54
D. Increasing Ka = decreasing pKa (inverse relationship)
pKa = -log (Ka)
E. The smaller the Ka, the weaker the acid
Ka = 10–pKa
F. The smaller the pKa, the stronger the acid

II. Example: Calculate the pH of a 1.00M solution of 𝐶𝐻3 𝐶𝑂𝑂𝐻 (𝑎𝑞)

A. 𝐶𝐻3 𝐶𝑂𝑂𝐻 + 𝐻2 𝑂 ⇌ 𝐻3 𝑂+ + 𝐶𝐻3 𝐶𝑂𝑂− (start by writing balanced AB rx)
I 1.00 0 0
C -x +x +x
E 1.00-x x x
 I = initial, C = change, E = equilibrium. Columns line up to equation. Ignore pure liquids
and solids.

𝒑𝒓𝒐𝒅𝒖𝒄𝒕𝒔 [𝐻3 𝑂 + ][𝐴− ] [𝐻3 𝑂+ ][𝐶𝐻3 𝐶𝑂𝑂 − ]

B. 𝐾𝑎 = 𝒓𝒆𝒂𝒄𝒕𝒂𝒏𝒕𝒔 = 𝐾𝑎 = [𝐶𝐻3 𝐶𝑂𝑂𝐻]
[𝐻𝐴]
(𝑥 )(𝑥)
1.8 𝑥 10−5 = To avoid using
1.00 − 𝑥
−5
𝑥2 quadratic formula,
1.8 𝑥 10 = assume x<<<1 so that
1.00
𝑥 = 0.0042 𝑀 = [𝐻3 𝑂+ ] we can say 1.00 – x = 1
𝑝𝐻 = − log[𝐻3 𝑂+ ] = − log(0.0042𝑀) = 2.38

Weak base equilibrium

I. 𝐵 + 𝐻2 𝑂 ⇌ 𝐵𝐻 + + 𝑂𝐻 −

II. Kb – the base ionization constant or base dissociation constant

[𝑩𝑯+ ][𝑶𝑯− ]
A. 𝑲𝒃 = 𝑩
B. The smaller the Kb, the weaker the base

III. 𝒑𝑲𝒃 = − 𝐥𝐨𝐠[𝑲𝒃] (so again, Kb and pKb have an inverse relationship)
A. The smaller the pKb, the stronger the base

IV. Ex. Calculate the pH of a 0.500M solution of 𝑁𝐻3 (𝑎𝑞)

A. 𝑁𝐻3 (𝑎𝑞 ) + 𝐻2 𝑂 ⇌ 𝑁𝐻4+ + 𝑂𝐻 −
I 0.500 0 0
C -x +x +x
E 0.500-x x x

[𝑁𝐻4+ ][𝑂𝐻 − ]
B. 𝐾𝑏 = [𝑁𝐻3 ] To avoid using quadratic
(𝑥 )(𝑥) formula, assume
1.8 𝑥 10−5 = x<<<0.500 so that we can
0.500 − 𝑥
𝑥2 say 0.500 – x = 0.500
1.8 𝑥 10−5 =
0.500
𝑥 = 0.0030 𝑀 = [𝑂𝐻 − ]
𝑝𝑂𝐻 = − log[𝑂𝐻 − ] = − log(0.0030𝑀) = 2.52
𝑝𝐻 + 𝑝𝑂𝐻 = 14.00
𝑝𝐻 = 11.48
 //// SECTION SUMMARY ////

Ka or Kb pKa pKb Examples to know Equation

Strong Ka>>1 Smallest Largest HClO4, HX(X= Cl, Br, I), pH = -log[H+] or -log[H3O+]
Acids H2SO4, HNO3

Weak Ka<<1 HCOOH, CH3COOH Ka = [H3O+][A–] / [HA]

Acids ⇩ ⇩
Weak Kb<<1 HF, HCN, H2S, H2O Kb = [BH+][OH–] / [B]
Bases

Strong Kb>>1 Largest Smallest NaOH, KOH, Ca(OH)2, pOH = -log[OH–]

Bases Mg(OH)2

//////

Relationship between Ka and Kb, and between pKa and pKb

pKa + pKb = 14.00

Ka x Kb = Kw = 1.0 x 10–14

This helps explain why a strong acid has a weak conjugate base, e.g.:

If you have a value for Ka or Kb, you can calculate the value of the other

Example: Kb for methylamine (CH3NH2) = 3.7 x 10–4. Find the Ka for the methylammonium ion
(CH3NH3+).
Ka x Kb = Kw
Ka (3.7 x 10–4) = 1.0 x 10–14
Ka = 2.7 x 10–11
Acid-base Properties of Salts

Key: Strong acid (SA), strong base (SB), weak acid (WA), weak base (WB)
Note: Na+ (sodium cations) don’t react with water

––1––
SA + SB → H20 + Salt
HCl + NaOH → H2O + NaCl

Strong acids create weak conj. base, and therefore neutral salts:
• Strong acids create weak conjugate bases (e.g. HCl, a strong acid, creates Cl–, a weak base).
• The weak base doesn’t take protons from water very well, so the pH is unaffected and the solution
containing H2O and NaCl remains neutral (pH = 7).
• SA + SB → H20 + Salt Creates neutral solution

––2––
WA + SB → Salt
CH3COOH + NaOH → CH3COO–Na+ (+ H2O when we are in an aqueous solution)

Weak acids create strong conj. base, and therefore basic solutions
• Since CH3COOH is a WA, it creates a strong conjugate base (CH3COO–)
• CH3COO–, the strong conjugate base, reacts with water.
• This creates CH3COOH and OH–, so our [OH–] has increased, so pH > 7
• This creates a basic solution.
• WA + SB → Salt Creates basic solution

––3––
SA + WB → salt
HCl + NH3 → NH4+Cl– (+ H2O when we are in an aqueous solution)

• The salt NH4+ will donate a proton to H2O, producing H3O+, so our [H3O+] has increase, so pH < 7
• This creates an acidic solution
• SA + WB → salt Creates acidic solution

pH of Salt Solutions

Example: Calculate pH of a 0.25M soln of CH3COONa(aq)

↳ Looks like CH3COO–Na+ in solution
● Method: Use equation Kb=[CH3COOH][OH-]/[CH3COO] to attain [-OH] to ultimately
calculate pH
● Step 1: Write equation
CH3COO– + H20 → CH3COOH + OH–
 ● Step 2: ICE Box (Initial, Change, Equilibrium)
I: 0.25 0 0
C: -x +x +x
E: 0.25 -x +x +x
● Step 3: Use Kb equation and assume x<<1, so 1-x ≈ 1
Why use Kb here not Ka? – Because CH3COO– is functioning as a base here.
Kb = [H30+][CH3COO-]/[CH3COOH]
Kb = (x)(x)/0.25
● Step 4: Since most books or examples won’t give us Kb, we need to use Ka to find Kb
Kw = Ka*Kb
1.0 x 10-14 = 1.8 x 10-5 * Kb
Kb = 5.6 x 10-10
● Step 5: Use known Kb to find [-OH]
5.6 x 10-10= x2/0.25
x = 1.2 x 10–5 of [OH–]
● Step 6: Use [OH–] to find pOH and pH
pOH= –log(1.2x10-5) = 4.92
pH=14 – 4.92 = 9.08

Common Ion Effect

Calculate pH of a solution that is 1.00 M CH3COOH (Ka = 1.8 x 10–5) and 1.00 M CH3COONa
● Method: Approach similarly with the ICE box, but add the additional source to the Initial
● Recall: CH3COONa ‘looks like’ CH3COO–Na+ in solution, so this amt will be added to RHS.
This is called the common ion effect because now there are two sources for the ion to be
added to the equation (ionization of acetic acid, and also the addition of sodium acetate)
● Step 1: Write equation
CH3COOH + H20 <--> H3O+ + CH3COO–
● Step 2: ICE Box (Initial, Change, Equilibrium)
I: 1.00 0 1.00
C: -x +x +x
E: 1.00-x +x 1.00+x
● Step 3: Use Ka equation and assume x<<1, so 1-x ≈ 1 and 1+x ≈ 1
Ka = [H30+][CH3COO-]/[CH3COOH]
Ka = (x)(1.00+x)/1.00–x Ka = (x)(1.00)/1.00

● Step 4: Use known Ka to find [H3O+]

Ka of acetic acid = 1.8 x 10–5
1.8 x 10–5 = (x)(1.00)/1.00
x = 1.8 x 10–5 M of H3O+
● Step 5: Use [H3O+] to find pH
pH= –log(1.8 x 10–5) = 4.74
Chemistry of buffer solutions

Buffer – an aqueous solution that resists changes in pH upon the addition of an acid or a base.

Adding water to a buffer or allowing water to evaporate from the buffer does not change the pH
of a buffer significantly.

Buffers are made up of pairs, such as:

• A WA and its conjugate base
o CH3COOH and CH3COO–
• A WB and its conjugate acid
o NH3 and NH4+
o HPO42– and H2PO4–

How does a buffer work?

• When a SB is added, the acid present in the buffer neutralizes the hydroxide ions (OH –)
• When a SA is added, the base present in the buffer neutralizes the hydronium ions (H 3O+)

Example 1:
Example 2:

Buffer capacity of a buffer:

Let’s assume our buffer is made up of a weak acid (HA) and its conjugate base (A –).

In this case, the equilibrium constant of the WA will be represented as:

The above expression can be rearranged to give:

Since Ka is a constant, [H3O+] will depend directly on the ratio of [HA]/[A–].

Since , the ratio of [HA]/[A–] directly influences the pH of a solution. In other

words, the actual concentrations of A– and HA influence the effectiveness of a buffer.
The more A– and HA molecules available, the less of an effect the addition of a strong acid or base
will have on the pH of the solution.

Example:
HCl (strong acid) added to a buffering system. Initially, the protons produced will be taken up by
the conjugate base (A–)

This will slightly change the pH by altering the ratio [HA]/[A–] as [A–] and [HA] are constantly
changing, but as long as there is enough A– present, the change in pH will be small.

However, if we keep adding HCl, eventually the A– will run out, and once there is no more A– left,
any HCl will donate its proton to water, which will dramatically increase the concentration of
[H3O+], leading to a drastic change in the pH of the solution.

SO, in order to be an effective buffer:

• Number of moles of the buffer’s weak acid and its conjugate base must be significantly
large compared to the number of moles of SA or SB that may be added.
• The best buffering will occur when the ratio of [HA] to [A–] is almost 1:1. In that case, pH
= pKa. Buffers are considered to be effective when the ratio of [HA] to [A –] ranges
anywhere between 10:1 and 1:10.
• A good buffer will have a pKa within 1 pH unit of desired experimental conditions

Henderson-Hasselbalch (HH) equation (& sample calculations)

HH equation: pH=pKa +log([A-]/[HA])

Example: pH of a buffer soln composed of 0.24M NH3 and 0.20M NH4+Cl–?

● Method: Use HH equation to find pH since we have a weak acid and its conjugate
base:
● Ka of NH4+ = 5.6 x 10–10 (given)
pKa = –log(Ka) = 9.25 Now we are set to use our HH equation

pH= pKa +log [A-]/[HA]

pH= 9.25 +log(0.24/0.20) = 9.33

Example: pH when you add 0.005 mol NaOH (base) to 0.50 L of the buffer soln
above?
● Step 1: Think about what component of the buffer the base is going to react with,
and write out the corresponding equation
NH4+ +OH– → H20 +NH3
 ● Step 2: Find molarity of NaOH
0.005 mol /0.5 L= 0.01M NaOH
● Step 3: ICE Box
NH4+ + OH– → H20 + NH3
I: 0.20 0.01 0.24
C: -0.01 -0.01 0.01
E: 0.19 0.25
● Step 4: Find pH using HH equation
pH= 9.25 + log(0.25/0.19)= 9.37 <-- note how pH only went up a little

Example: pH when you add 0.03 mol HCl (acid) to 0.50 L of the original buffer soln?
● Step 1: Think about what component of the buffer the base is going to react with,
and write out the corresponding equation
NH3 + H3O+ → H20 + NH4+
● Step 2: Find molarity of HCl
0.03 mol / 0.5 L= 0.06 M HCl
● Step 3: ICE Box
NH3 + H3O+ → H20 + NH4+
I: 0.24 0.06 0.20
C: -0.06 -0.06 +0.06
E: 0.18 0 0.26
● Step 4: Find pH using HH equation
pH= 9.25 + log(0.18/0.26)= 9.09 <-- note how pH only went down a little

Blood buffering

The major physiological buffer of blood pH is the carbonic acid (H2CO3) – bicarbonate ion
(HCO3–) system.

When any acidic substance enters the bloodstream, the bicarbonate ions neutralize the
hydronium ions forming carbonic acid and water. Carbonic acid is already a component of the
buffering system of blood. Thus, hydronium ions are removed, preventing the pH of blood from
becoming acidic.
On the other hand, when a basic substance enters the bloodstream, carbonic acid reacts with the
hydroxide ions producing bicarbonate ions and water. Bicarbonate ions are already a
component of the buffer. In this manner, the hydroxide ions are removed from blood, preventing
the pH of blood from becoming basic.

Naturally, the process of neutralizing hydronium ions or hydroxide ions leads to fluctuations in
the concentrations of the components of the buffering system, but this is fine so long as the
buffering mechanism has effectively maintained blood pH at ~7.4, such that acidosis and
alkalosis have been prevented.

If blood pH dips below 6.8 or rises above 7.8, cells can stop functioning and the individual can
die.

Enzymes function optimally at a particular pH and temperature. Alterations in pH can cause

enzymes to stop working or become permanently denatured, disabling their catalytic activity,
which disturbs biological processes and can lead to various diseases.

Titrations
o Purpose of titration: to determine the concentration of a solution with an unknown
concentration

o Components a titration:
○ Tritrand/Analyte → known volume, unknown concentration
○ Titrant → known volume, known concentration
○ Equivalence point → the point at which amount of titrant added is just enough to
completely neutralize the analyte solution
■ At the equivalence point, moles of base = moles of acid
■ Resulting solution contains only salt and water
■ Equivalence point on a titration curve is halfway up the steep part of the
curve (will become relevant later)

o Acid-base titrations are monitored by the change of pH as titration progresses

○ Indicator → a weak acid or base that is added to the analyte solution and changes
color at the equivalent point (i.e. the point at which the amount of titrant added is
just enough to completely neutralize the analyte solution).
■ Choose indicator that changes color in the range near your equivalence
point.
■ The indicator allows us to visually spot the equivalence point.
○ Endpoint → simply refers to the point at which the indicator changes color
 EXAMPLE 1 (using SA and SB, and 1:1 molar relationship)

To find [HCl] of 20.0ml that had 48.6ml of 0.100M NaOH titrant

Step 1: Write equation

HCl + NaOH → H2O +NaCl

Step 2: Find mols of titrant

[NaOH] = 0.100 M = x mol/ 0.0486L =0.00486 mol NaOH

Step 3: Using molar ratio find moles of Tritrand

Since 1:1 ratio, there is 0.0486 mol of HCl

Step 4: Use known volume of unknown to find concentration

[HCl] = 0.00486/0.0200 L = 0.243 M

Shortcut (only works if you are using a SA and a SB in a 1:1 molar relationship)
Molarity x Volume=Molarity x Volume
MacidVacid = MbaseVbase

x(10ml)=(0.100M)(48.6ml)
x = 0.243 M
 EXAMPLE 2 (not a 1:1 molar relationship:)

In a titration, 27.4 mL of a 0.0154 M solution of Ba(OH)2 is needed to neutralize 20.0 mL of HCl.

What was the concentration of the acid solution?

Step 1: Write equation and balance

Ba(OH)2 + 2 HCl ––> 2 H2O + BaCl2

Step 2: Find mols of titant

[Ba(OH)2] = 0.0154 M = mol / L
0.0154 M = mol / 0.0274 L
mol = 0.000422 mol of Ba(OH)2

Step 3: Using molar ratio find moles of Tritrand

Ba(OH)2 + 2 HCl ––> 2 H2O + BaCl2
Ratio: (OH)2 1:2 HCl
0.000422 mol of Ba(OH)2
0.000422(2) = 0.000844 mol of HCl
Step 4: Use known volume of unknown to find concentration
0.000844 mol / 0.0200 L = 0.0422 M

You can technically still use the MV = MV shortcut here, but because the molar ratio between the
acid and base are not equal, you would need to adjust the answer according to the molar
ration (e.g. in the last example, you would multiply by 2):

Mbase x Vbase = Macid x Vacid

(0.0154 M)(27.4 mL) = x(20.0mL)
x = 0.0211M
2x = 0.0422 M

///
 o Titration curve – a plot of the pH of the analyte solution (y-axis) vs. the volume of titrant
added as the titration progresses (x-axis)

Examples of titration curves:

○ SA-SB (e.g. HCl + NaOH)

■ Point #1: No SB added yet. Low initial point because strong acid
dissociates almost 100% to H3O+
■ Point #1 –– #2: As NaOH is added dropwise, H3O+ slowly starts getting
consumed by OH– produced by dissociation of NaOH. However, analyte is
still acidic due to the predominance of H3O+ ions.
■ Point #3: Equivalence point (halfway up the steep curve). All H3O+ ions are
completely neutralized by OH– ions, so the solution has only salt (NaCl) and
water, and therefore a neutral pH = 7
■ Point #4: Addition of NaOH continues, so pH starts to become basic, since
HCl has been completely neutralized and now excess OH– ions are present
in the solution (formed from the dissociation of NaOH)
○ WA-SB (e.g. CH3COOH + NaOH)

■ Point #1: pH starts slightly higher than in the previous case, since WAs do
not completely dissociate to H3O+ in solution.
■ Point #3: pH is not neutral at equivalence point, pH >7 because the
conjugate base (CH3COO–) of a weak acid (CH3COOH) is a strong base. This
strong base will react with H2O to produce OH–, thus increasing the pH at
the equivalence point.

Compared to our first example using SA-SB:

○ SA-WB (e.g. HCl + NH3)

 ■ Point #3: pH is not neutral at equivalence point, pH<7. All H3O+ ions are
completely neutralized by NH3, and the solution only contains NH4+ and Cl–.
Since the conjugate acid (NH4+) of a WB (NH3) is a strong acid, NH4+ will
react with H2O to produce H3O+ ions, making the solution acidic.
■ Point #4: Because of weak base the excess does not increase as high as a
strong base

Compared to our first example using SA-SB:

○ WB-WA (e.g. CH3COOH + NH3)

■ Note: WB is the analyte, WA is the titrant.

■ No steep parts /steep changes in pH anywhere in the plot
■ Not much information can be extracted from such a curve.

SUMMARY: What can we learn from titrations and titration curves?

o The equivalence point of an acid-base reaction tells us the point at which the
amounts of acid and of base are just sufficient to cause complete neutralization, which
allows us to determine the starting concentration of the analyte solution.
o The pH of the solution at the equivalence point can tell us the strength of the acid
and strength of the base used in the titration:
○ SA-SB titration: pH = 7 at equivalence point
○ WA-SB titration: pH > 7 at equivalence point
○ SA-WB titration: pH < 7 at equivalence point

V. useful KA text-based page for any clarification needed on titrations:

http://tinyurl.com/kbpdshd
 Choosing an indicator

Want to use an indicator that changes color in the range of your equivalence point

Kind of pH at Which indicator Range of pH Color change

titration equivalence to use over this pH
point range

SA-SB pH = 7 Bromothymol 6-8 Yellow → Blue

blue

WA-SB pH > 7 Phenolphthalein 8-10 Clear → Pink

WB-SA pH < 7 Methyl Red 4-6 Red → Yellow

 Redox reactions

OIL RIG – oxidation is loss (of electrons), reduction is gain (of electrons).

Balancing simple redox reactions (using the half-reaction method):

Full, unbalanced reaction:

Reduction half-reaction:

Oxidation half-reaction

Multiple each reaction through to ensure that the number of electrons on each side are balanced
such that they can be canceled in the final equation:

Now simply add these newly-multiplied reactions together to get the overall balanced reaction:

This is just a simple example, since all the components are either free elements (oxidation
number of 0) or monatomic ions (whereby the oxidation number equals the charge of the ion).

Rules for Oxidation Numbers

1. The oxidation number of a free element is always 0.
2. The oxidation number of a monatomic ion equals the charge of the ion.
3. The oxidation number of H is +1 (-1 when combined with less electronegative elements).
4. The oxidation number of O in compounds is usually -2, but it is -1 in peroxides.
5. The oxidation number of a Group 1 element in a compound is +1.
6. The oxidation number of a Group 2 element in a compound is +2.
7. The oxidation number of a Group 17 element in a binary compound is -1.
8. The sum of the oxidation numbers of all of the atoms in a neutral compound is 0.
9. The sum of the oxidation numbers in a polyatomic ion is equal to the charge of the ion.
 Extra notes on redox reactions

You can assign oxidation numbers without the above rules, simply in the following way:
• Use EN to assign electrons in bonds to the most EN atom of the two, then count up
• Minus your count from the number of valence electrons that the atom should have (from
main group number on periodic table)
• Example – Assigning the oxidation number to oxygen in three different molecules:

Disproportionation reactions – a redox reaction whereby one substance is both oxidized and
reduced in the same reaction

Example:

Balancing redox reactions in general - write the half reactions, and for each half-reaction, do the
following:
 Back to redox reactions during titrations

Example:

LHS: Oxygen in a compound has an oxygenation state of –2. In MnO4– there are four oxygens, so
4x–2 = 8. Since the formal charge of the MnO 4– is –1, Mn must have an oxidation state of +7
(following rule 9, which states that the sum of the oxidation numbers in a polyatomic ion is equal
to the charge of the ion).

RHS: Mn2+ has a formal charge of +2, meaning that the +7 became +2 in the reaction, which is a
gain of electrons and thus Mn got reduced (making Mn the oxidizing agent)

LHS: Fe2+ has a formal charge of +2

RHS: Fe3+ has a formal charge of +3. Since +2 became +3, it can be said that Fe lost an electron,
and therefor Fe was oxidized (making Fe the reducing agent)

If we were not given the balanced equation and were required to balance it ourselves, the half
reactions would look like:
• Fe2+ ––> Fe3+ + 1e– x 5 to balance electrons, then add equations together
• Mn + 5e ––> Mn
7+ – 2+
Redox titrations

Continuing example from above:

MnO4– is the titrant (known concentration, known volume)

Fe2+ is the analyte (unknown concentration, known volume).

Since MnO4– is purple, and the products of the rx are colorless, the end point of the titration
occurs when the purple color persists after adding a drop of MnO 4–, because this indicates that
we have completely reacted all of the Fe2+ that we can present at the beginning, and there is
none left over to react with MnO4–

From this we can determine the concentration of Fe2+ in the original analyte solution using the
same methods as before, remembering to consider the balanced redox reaction:
• Use M and L to find moles of MnO4–
• Multiply moles of MnO4– by 5 (refer back to stoichiometry in balanced equation)
• Use original L of Fe2+ and newly found moles to determine M of Fe2+ in the original
solution.
• Modified MbaseVbase = MacidVacid shortcut could have been used here, provided we
multiplied x by 5 at the end.
Solubility Equilibria

Common polyatomic ions

• Cations:
o NH4+ Ammonium
• Anions:
o CH3COO– Acetate
o CN– Cyanide
o OH– Hydroxide
o MNO4– Permanganate

o NO3– Nitrate (-ate ‘more oxygens’)

o NO2– Nitrite (-ite ‘less oxygens’)

o ClO4– Perchlorate (Per- ‘one more oxygen’) –|

–
o ClO3– Chlorate (-ate ‘more oxygens’) | Works for Bromine too
–
o ClO2– Chlorite (-ite ‘less oxygens’) |
o ClO– Hypochlorite (Hypo- ‘one fewer oxygen’) –|

o SO42– Sulfate
o SO32– Sulfite
o HSO4– Hydrogen sulfate / Bisulfate

o CO32– Carbonate
o HCO3– Hydrogen carbonate / Bicarbonate
o PO43– Phosphate
o HPO42– Hydrogen phosphate
o H2PO4– Dihydrogen phosphate

o CrO42– Chromate
o Cr2O72– Dichromate
o C2O42– Oxalate
o O22– Peroxide

o SCN– Thiocyanate (Thio- – relates to sulphur)

o S2O32– Thiosulfate (Thio- – relates to sulphur)

o Note how the formal charge increased by +1 in the cases where hydrogen (H+) is
added – logical.
Dissolution and precipitation

Dissolution – Solute (e.g. salt; NaCl(s)) dissolves in a solvent (e.g. H2O)

NaCl(s) ––H2O––> Na+(aq) + Cl–(aq)

NaCl is an ionic crystal, held together by ionic bonds (Na+ and Cl– attracted to each other by charge).

H2O is a polar molecule; oxygen is more electronegative than the hydrogens, so the oxygen gets a
partial negative charge, and the hydrogens get a partial positive charge.

Ion-dipole interactions: the negative charge on the oxygen interacts with the positive charge on the
sodium cation, ‘pulling it off of’ the NaCl. The H2O is the dipole, and the ion is the Na+ cation.

Ion-dipole interactions: likewise, the positive charge on the hydrogens interacts with the negative
charge on the chloride anion. The H2O is the dipole, and the ion is the Cl– cation.
These ion-dipole interactions allow for the process of hydration: The water molecules break the ionic
bond, pull the Cl– and Na+ ions apart and surrounding them. This allows our ions to be stabilized by a
shell of our solvent molecules.

––––

Precipitation – the opposite of dissolution. Ions come together to fold a solid, which spontaneously
falls out of solution.

Add the contents of each beaker to combine the solution. What happens?

• Volume increases
• Precipitate forms (a white solid in this case)
o Ag+ and Cl– interact to form our precipitate: AgCl(s)
o Na+ and NO3– remain in solution.
For the precipitate to form, the electrostatic attractions of the ionic crystal (AgCl) must be stronger
than the forces of hydration, in order to ‘draw’ these ions out from their interactions with water

Ions that don’t take part in this reaction and just remain in solution (e.g. Na+ and NO3+) are called
spectator ions, and are not included in the net ionic equation:

Introduction to solubility and solubility product constant

Example: 10g of solid PbCl2 added to 50 mL of water at 25oc. Only 0.22 g of the solid
goes into solution.

a) Calculate the solubility (in both g/L and in mol/L) of PbCl2 in water at 25oc.

Solubility in g/L
0.22g / 0.0500 L = 4.4 g/L

Solubility in mol/L
Molar mass of PbCl2 = 207.2 + 2(35.45) = 278.1 g/mol

Moles of PbCl2 = 0.22 g / 278.1 g/mol = 0.00079 mol

0.00079 mol / 0.0500 L = 0.016 mol/L = 0.016 M

 b) Calculate the solubility product constant Ksp for PbCl2 at 25oc

PbCl2(s) <–––> Pb2+(aq) + 2Cl–(aq)

I 0 0
C – 0.016 + 0.016 + 0.016*2
E 0.016 0.032
Ksp = [Products] / [Reactants]

Ksp = [Pb2+]1 [Cl–]2

NOTE: Raise the concentration to the power of the coefficient

NOTE: Pure solids and pure liquids are left out of the equilibrium equation, so there is no
denominator in this case.

Ksp = (0.016)1 (0.032)2 = 1.6 x 10–5

c) How would the results change if we had try to dissolve 100g of solid PbCl2 in the 50 mL of
water at 25oc?

Still, only 0.22g would dissolve in our 50 mL of water, so we would just have a bigger pile of
undissolved PbCl2. Thu, molar solubility stays the same, and Ksp stays the same. This tells us that the
amount of undissolved solid has no influence on molar solubility or K sp.
Solubility from the solubility product constant

Example: Calculate the solubility of copper (II) hydroxide (Ksp = 2.2 x 10–20 at 25oc)

1) Step 1: Write balanced equation

Cu2+ OH– are the ions, so to balance charges, the chemical formula must be Cu(OH)2(s)

Cu(OH)2(s) <––> Cu2+(aq) + 2OH–(aq)

2) Step 2: ICE table

Cu(OH)2(s) <––> Cu2+(aq) + 2OH–(aq)

I 0 0

C -x +x +2x

E x 2x

3) Step 3: Solve for x using known Ksp

Ksp = [Products] / [Reactants] Exclude pure solids and pure liquids, add coefficients as exponents

Ksp = [Cu+]1 [OH–]2

2.2 x 10–20 = (1x)1 (2x)2

2.2 x 10–20 = (1x)(2x)(2x)

2.2 x 10–20 = 4x3

x = 1.8 x 10-7 M (molar solubility of Cu(OH)2)

4) Step 4: Convert molar solubility to solubility in g/L (if question requires)

Molar solubility of Cu(OH)2 = 1.8 x 10-7 M or mol/L (from before)

Molar mass of Cu(OH)2 = 97.59 g/mol (from periodic table)

Multiple the two and the ‘mol’ cancel to give g/L:

1.8 x 10-5 g/L Meaning that in 1L of solution, you can only dissolve 1.8 x 10-5g of Cu(OH)

i.e. Cu(OH)2 is not very soluble in solution.

Solubility from the common-ion effect
Calculate the solubility of copper (II) hydroxide (Ksp = 1.6 x 10–5 at 25oc) in a 0.100 M solution of KCl.

Recall: common-ion effect occurs when there are multiple sources of a common ion. In this case, our
common-ion is Cl–.

Approach this question the problem given two lectures ago, but this time integrate the fact that
there is already some Cl– in solution to begin with (from the dissociation of KCl ––> K+ and Cl– in
solution)

PbCl2(s) <–––> Pb2+(aq) + 2Cl–(aq)

I 0 0.100
C –x +x + 2x
E x 0.100 + 2x
Ksp = [Products] / [Reactants] Exclude pure solids and pure liquids, add coefficients as exponents

Ksp = [Pb2+]1 [Cl–]2

1.6 x 10–5 = (x)1 (0.100 + 2x)2 Assume that x is negligible enough to simplify 0.100 + 2x to 0.100

1.6 x 10–5 = (x)1 (0.100)2

1.6 x 10–5 = 0.01x

x = 0.0016 M Solved for molar solubility for PbCl2 ions in solution of KCl.

Molar solubility is decreased compared to this scenario in H2O.

This is due to the presence of the common ion (Cl –) here.

Solubility from the pH of the solution

CaF2(s) <––> Ca2+(aq) + 2F–(aq) CaF2 is not completely dissolving in solution.

However, when we add some acid (i.e. a source of H+), CaF2 can now completely
dissolve.

What’s happening here?

Adding H+ to the H2O-containing solution leads to the formation of hydronium ions
(H3O+aq) in the solution.

Since F– ions (acting as a base) are present too, we can predict that the following will
happen:

2H3O+(aq) + 2F–(aq) ––> 2HF(aq) + 2H2O

Thus, addition of H+ to the system is causing a decrease in one of our products from
the original equation (i.e. the F–), so equilibrium will shift to the right to make more of
our product, which makes more CaF2 dissolve, meaning that we have increased the
solubility of CaF2.

Since the 2F– on either side of these two equations cancel, our net reaction looks like
this:
CaF2(s) + 2H3O+(aq) <––> Ca2+(aq) + 2HF(aq) + 2H2O

By adding acid (i.e. adding a proton source, or decreasing pH), we have increased the
solubility of CaF2
–––
However, this isn’t always true – it depends on what compound you’re talking about.

AgCl(s) <––> Ag+(aq) + Cl–(aq)

Cl– is a very weak base, unlike the F– seen in the last example. Thus, when acid is added
and H3O+ forms, Cl– doesn’t react with the hydronium (H3O+).

This means that no product (Cl–) is sequestered, and no shift in equilibrium occurs,
meaning that no change in the solubility of AgCl(s) occurs.

Take-home message: A change in solubility depends on the strength of the base, i.e.
whether or not the base is strong enough to interact with the acid that you’re adding.
Solubility and complex ion formation

Calculate the molar solubility of AgCl (Ksp = 1.8 x 10–10 at 25oc):

(a) in pure water

AgCl(s) <––> Ag+(aq) + Cl–(aq)
I 0 0
C -x +x +x
E x x

Ksp = [Products] / [Reactants] Exclude pure solids and pure liquids, add coefficients as exponents

Ksp = [Ag+]1 [Cl–]1

1.8 x 10–10 = x2

x = 1.3 x 10–5 M <–– Molar solubility of AgCl2

(b) in 3.0 M NH3

Ag+(aq) + 2NH3(aq) <––> Ag(NH3)2+(aq) Kf = 1.6 x 107 <– Kf is the formation constant
^ complex ion formed by a Lewis acid-base reaction

Ag+ is the Lewis acid because it is the electron pair acceptor.

NH3 is the Lewis base because it is the electron pair donor.

Since the formation constant (Kf) is so high, equilibrium lies far to the right of this
equation. Thus, this reaction ‘picks up’ Ag+ cations and removes them from solution.

This decreases the concentration of one of the products (Ag+) in the original equation,
and thus equilibrium in that equation will shift to the right, which increases the
solubility of AgCl(s)
NET REACTION when AgCl is added to NH3:

Ag+ on both sides, so they cancel.

When you add two reactions together, you multiple their equilibrium constants
together to get the new equilibrium constant (K = Ksp x Kf)

We can now create an ICE table:

Recall from before: molar solubility of AgCl2 in pure water was very low (1.3 x 10–5 M).

Compare this to our new molar solubility (0.14 M) in NH3.

Conclusion: the formation of the complex ion Ag(NH3)2 increased the solubility of the
slightly soluble compound AgCl2.
Stoichiometry and empirical formulae

Tools common to all types of stoichiometry:

• Dimensional analysis (allows conversion from unit to unit)
• Avogadro’s number (allows conversion between moles and the number of
atoms, molecules, or ions)
• Molecular weight (allows conversion between mass and moles)

Calculating mole fraction

Example: calculate the mole fraction of Cd(NO3)2 in a 12% (wt-wt) aqueous solution.

12% (wt-wt) simply means that by weight, 12% of the solution is solute.

1) Step 1: Make calculations easy:

• For easy of calculations, assume that we have 100g of the substance, and thus
there is 12g of solute and 88g of water.

2) Step 2: Determine molecular weights of the substance and water using the periodic
table.
• MWCd(NO3)2 = 236 g/mol
• MWH2O = 18 g/mol

3) Step 3: Use g/mol and g to find mol of each

• 12 g / 236 g/mol = 0.05 mol of Cd(NO3)2
• 88 g / 18 g/mol = 5 mol of H2O

4) Step 4: Find mole fraction

• Numerator: moles of substance of interest
• Denominator: moles of the two substances combined

0.05 mol .
0.05 mol + 5 mol = 0.01, or 1%
 Calculating the number of particles
Example: Approximate the number of ammonium ions in 6 mL of a (NH 4)3PO4•3H2O
solution prepared by dissolving 4.0g of ammonium phosphate trihydrate in enough
water to make 25 mL of the solution.

1) Step 1: Determine MW of ammonium phosphate trihydrate

MW(NH4)3PO4•3H2O = 203 g/mol

2) Step 2: Use g/mol and g to find mol

(4.0 g) / (203 g/mol) = 0.02 moles in 25 mL of solution.

3) Step 3: Find out how many moles are in 6 mL of solution

0.02 mol / 25 mL = x mol / 6 mL
x = 0.005 mol

4) Step 4: Multiply by Avogadro’s number to find the number of molecules or ions

0.005 mol x (6.023 x 1023 molecules/mol) = 3x1021 molecules.

• Math trick here:
o Put 0.005 mol into scientific noation: 5 x 10–3
o Now the multiplication looks like: 5 x 10–3 x 6 x 1023
o Or even: 5 x 6 x 10–3 x 1023
o Recall: (nx)(ny)=nx+y
o 5 x 6 x 10–3 x 1023 = 30 x 1020 = 3 x 1021

5) Step 5: Consider that there are three ammonium ions that dissociate into solution
when dissolved:

3 ions/molecule x (3 x 1021 molecules) = 9 x 1021 ammonium ions

 Solving across the equation using stoichiometric coefficients

Given , calculate how many mL of a 4 M

solution of NaOH are required to produce 4.5 L of H 2.

1) Step 1: Find mol of H2 needed

1 mol of an ideal gas at STP (standard temperature/pressure) has a volume of 22.4 L.

(1 mol) / (22.4 L) = (x mol) / (4.5 L)

x = 0.2 mol of H2 needed

2) Step 2: Find mol of NaOH needed

Equation tells us: 6 mol of NaOH / 3 mol H2

(6 mol NaOH) / (3 mol H2) = (x mol) / (0.2 mol)

x = 0.4mol of NaOH needed.

3) Step 3: Find L of NaOH need from mol and M (i.e. mol/L)

Recall: M is mol/L.

4 mol/L = 0.4 mol / x

x = 0.10 L or 100 mL of NaOH <- final answer

Can be done all in one calculation:

 Empirical formulae

Empirical formula – the simplest ratio between the elements in a compound

Molecular formula – the actual number of atoms in a compound

Molecular may be equivalent to the empirical formula (e.g. formaldehyde, CH 2O), or may be some
multiple of the empirical formula (e.g. glucose, C 6H12O6). Thus, formaldehyde and glucose have the
same empirical formula but different molecular formulas.

To convert empirical -> molecular formula, we need the MW of the compound.

The find empirical formula, we need the mass composition of a compound given as either grams or
mass percentages.

Example: Find the empirical formula of a compound that has a mass composition of 44.7% C, 7.5% H,
and 47.8% O.

Numerator is what was given (if you make the match easier and assume perctnages of 100g)
Denominator is taken from periodic table (g/mol)

Now multiply to get whole number ratios:

Now divide by anything common (in this case: 3) to find the empirical formula to be C5H10O4
 Transaminase reaction

Transaminase reaction, catalyzed by aspartate transaminase (AST) in our liver:

Aspartate α-kg glutamate oxaloacetate

Concentration of AST: 1 mg/mL in 0.1 M of buffer solution of potassium phosphate, pH 7.5.

Buffer solution further diluted to 0.05-0.25 ug/mL

3.3g of aspartate (C4H7NO4) and 7.3g of α-kg (C5H6O5) are added to the mix.

After incubation, 2.4g of pure glutamate (C5H9NO4). The other product in the reaction is oxaloacetate
(C4H4O5)

Calculating mass percent

Example: Which of the four compounds has the greatest mass percent of oxygen?

Step 1: Caluclate MW of all the compounds using period table.

Step 2: Approximate mass percents

For the MCAT, you won’t need to determine the actual value, just a good approximate. Try to
approximate the numerator and denominator by substituting numbers that are easier to handle with
your head but remain as close as possible to the original numbers.

Thus, we would select oxaloacetate (C4H4O5) as our answer choice.

Calculating limiting reactant

Example 1: Calculate the limiting reactant of the transamsinase reaction

Step 1: Calculate how many moles of each of the reactants you have.

Recall – here is our equation:

Since the stoichiometry of the reaction is 1:1, so C 4H7NO4 is our limiting reactant.

–––––
Example 2: Calculate the limiting reactant of this more complicated example:

Step 1: Calculate how many moles of each of the reactants you have.

Step 2: Divide each by its stoichiometric coefficient to find the limiting reagant:
Q: How much P4 remains after the reaction?

Step 3: Determine how much P4 was used in the rx

(0.10 mol of KClO3) / (10) = (x mol of P4) / (3)

x = 0.03 mol P4 reacted

Step 4: Subtract how much P4 was used in the rx from the number of moles of P4 that we determined
were present

0.33 mol – 0.03 mol = 0.30 mol of P4 remaining

Theoretical yield

Example: find the percent yield of glutamate in the transaminase experiment from before.

3.3g (0.025 mol) of aspartate (C4H7NO4) and 7.3g (0.05 mol) of α-kg (C5H6O5) to start with.

After incubation, 2.4g of pure glutamate (C5H9NO4). The other product in the reaction is oxaloacetate
(C4H4O5)

Step 1: Find theortetical yield

Recall: aspartate was our limiting reagent, as was present in a quantity of 0.025 mol.

Since the stoichiometry for aspartate and glutamate is 1:1, we will produce 0.025 mol of glutamate.

0.025 mol * 147 g/mol ≈ 3.75 g of glutamate

Tip to do this kind of calculation without a calculator:

• Assume 147 ≈ 150
• 0.025 * 150 = 2.5 x 10–2 x 150 = 2.5 * 150 * 10–2 = (300+75) x 10–2 = 3.75

Step 2: Compare theoretical yield to actual yield (given in the question)

Theoretical yield = 3.75 g

Actual yield (given in question) = 2.4 g
Percent yield = 2.4 / 3.75 g ≈ 2.4 / 3.6 g = 2/3, which is 0.66 or 66%
Dot Structures

Drawing dot structures

Steps:
(1) Find total number of valence electrons (VE)
• Use periodic table in the following way to find valence electrons of the
atoms:
Max # v.e.
in shell

2 e–
8 e–

• Helium (He) not shown above, but has 2 electrons per shell

• Add an electron for every negative charge

• Take away an electron for every positive charge.

(2) Decide the central atom based on electronegativity (the least electronegative,
IGNORING HYDROGEN, will be the central atom), draw bonds, and then
subtract the electrons used (from drawing the covalent bonds, which each
count as two VE) from the total number of VE we found in step 1.

• Trend of electronegativity:
 (3) Assign left over VE to the terminal atoms, and then subtract the electrons from
the total left over in step 2.

(4) If necessary, assign any leftover electrons to the central atom.

Also, check that central atom satisfies octet rule (if applicable).
• If central atom doesn’t have an octet, create multiple (i.e. double or triple)
bonds (unless this messes up an already established formal charge of 0)
• If the central atom already has an octet or exceeds an octet, you are usually
done (though check for formal charges – next lecture)

Example: SiF4
Step 1:
Si has 4 VE
F has 7 VE
4 VE + 4(7 VE) = 32 VE

Step 2:
S is the least electronegative of the two, so it becomes our central atom.

Each covalent bond counts as 2 VE, so 32 VE – 4(2 VE) = 24 VE left

Step 3:
Terminal atoms are F here. Since F is at the second level down on the periodic
table, it has the capacity to accommodate 8 VE, and it already has 2 VE, so we
need to add 6 lone VE to satisfy the octet rule.

24 VE – 4(6 VE) = 0 VE left over.

Step 4:
Si already has an octet, so we are done.
 Example: CH2O
Step 1:
C has 4 VE
H has 1 VE
O has 6 VE
4 VE + 2(1 VE) + 6 VE = 12 VE

Step 2:
Ignoring H, C is the least electronegative out of C and O, so it becomes our
central atom

Each covalent bond counts as 2 VE, so 12 VE – 3(2 VE) = 6 VE left over.

Step 3:
Terminal atoms are O and H here.

Since H is at the first level down on the periodic table, it only has the capacity to
accommodate 2 VE, and it already has 2 VE, so it is at full capacity and can be
left untouched.

Since O is at the second level down on the periodic table, it has the capacity to
accommodate 8 VE, and it already has 2 VE, so we need to add 6 lone VE to
satisfy the octet rule.

6 VE – 6 v.e = 0 VE left over.

Step 4:
C needs to follow the octet rule, but currently doesn’t, so we need to give it an
octet by creating multiple bonds.
 Finished dot structure

Example: XeF5+
Step 1:
Xe has 8 VE
F has 7 VE
Positive charge means that we lost an electron.
8 VE + 5(7 VE) – 1 VE = 42 VE

Step 2:
Xe is the least electronegative of the two, so it becomes our central atom

Each covalent bond counts as 2 VE, so 42 VE – 5(2 VE) = 32 VE left over.

Step 3:
Terminal atoms are F

Since F is at the second level down on the periodic table, it has the capacity to
accommodate 8 VE, and each already has 2 VE, so we need to add 6 lone VE to
satisfy the octet rule.
 32 VE – 5(6 v.e) = 2 VE left over.

Step 4:
Since we have 2 VE left over, we need to assign them to the central atom

Finished dot structure

No problem that Xe is violating the octet rule, because it doesn’t apply (since Xe
is past the second level of the periodic table)

Some people will add the following to represent that the molecule is an ion:
Terminology:
• Bonding electrons – electrons participating in a bond between two atoms.
Represented by lines.
• Non-bonding electrons, or lone-pair electrons – electrons that are not
participating in bond formation. Represented by dots.

Formal charge and dot structures

Formal charge = (# VE in free atom) – (# VE in bonded atom)

Formal charge = (# VE from the periodic table) – (# VE from our diagram)

Example: NH4+

Assigning formal charges:

First, draw on dots for the covalent bonds like so:

For each covalent bond, assign 1 VE to each of the atoms, like so:
Now we can assign formal charges to our atoms
Formal charge = (# VE in free atom) – (# VE in bonded atom)
Formal charge of N = 5 – 4 = +1
Formal charge of H = 1 – 1 = 0

Final dot structure should look like this:

Example: H2SO4

In this case, the ‘top’ and ‘bottom’ oxygens on our diagram would have a formal
charge of –1, and our central sulfur would have a formal charge of +2.

Our goal is to minimize the formal charges, which can be done in the following way:
If you re-count the formal charge, you’ll find that every atom in the molecule has a
formal charge of 0, which is desired.

It’s okay for sulfur to have more than an octet, because it has an expanded valence
shell, but this is fine because it’s in the third level of the periodic table.

Resonance structures

When more than one dot structure can be drawn, the molecule or ion is said to have
resonance.

The individual dot structures are termed contributing resonance structures

Example: NO3–

The central atom, N, doesn’t yet have an octet, but ‘wants’ one as it’s in the second
row of the periodic table. There are three ways to accomplish this:
 Resonance structures of each other (indicated by double-ended arrows)

Instead of thinking of it being like the structure resonates between the three, think of
it like a resonance hybrid of these three dot structures, with the electrons delocalized
and spread out across all three oxygens, producing a bond that is stronger than a
single bond but weaker than a double bond:

We know that it’s more like this resonance hybrid rather than transitioning between
three different structures, because when we measure bond length of the three bonds,
they are equal. If it was a transitioning-type reality, we would expect one bond (the
double bond) to be shorter than the other two (single bond), which is not what we see.

VSEPR for 2 electron clouds

VSEPR – Valence shell electron pair repulsion

• Since electrons are negatively charged, they will repel each other.
• This repulsion will cause the molecule to have a particular shape.
Predicting the shapes of molecules and ions:
(1) Draw a dot structure to show the valence electrons
(2) Count the number of “electron clouds” (regions of electron density) surrounding
the central atom
(3) Predict the geometry of the electron clouds around the central atom
(4) Ignore any lone pairs and predict the geometry of the molecule/ion

Example: BeCl2

(1) Draw a dot structure to show the valence electrons

(2) Count the number of “electron clouds” (regions of electron density)

surrounding the central atom

Two electron clouds.

(3) Predict the geometry of the electron clouds around the central atom

These electron clouds ‘want to be’ as far away from each other as possible, so
will lie opposite from each other.

(4) Ignore any lone pairs and predict the geometry of the molecule/ion

Molecule assumes a linear conformation (bond angle = 180°)

 Example: CO2

(1) Draw a dot structure to show the valence electrons

(2) Count the number of “electron clouds” (regions of electron density)

surrounding the central atom

Two electron clouds.

(3) Predict the geometry of the electron clouds around the central atom

These electron clouds ‘want to be’ as far away from each other as possible, so
will lie opposite from each other – electron clouds assume a linear
conformation.

(4) Ignore any lone pairs and predict the geometry of the molecule/ion

No lone pair of electrons, so molecule is also said to assumes a linear

conformation (bond angle = 180°)
 VSEPR for 3 electron clouds

Example: BF3
(1) Draw a dot structure to show the valence electrons

(2) Count the number of “electron clouds” (regions of electron density)

surrounding the central atom

3 electron clouds.

(3) Predict the geometry of the electron clouds around the central atom

The way that these 3 electron clouds can get as far away from each other as
possible is in a conformation known as trigonal planar:

(4) Ignore any lone pairs and predict the geometry of the molecule/ion

No lone pair of electrons, so molecule also said to assumes a trigonal planar

conformation (bond angle = 360/3 = 120°)
 Example: SO2

(1) Draw a dot structure to show the valence electrons

(2) Count the number of “electron clouds” (regions of electron density)

surrounding the central atom

3 electron clouds.

(3) Predict the geometry of the electron clouds around the central atom

Electron clouds have a trigonal planar geometry

(4) Ignore any lone pairs and predict the geometry of the molecule/ion

If you ignore the lone pairs and pretend they aren’t there, what does the actual
molecule/ion look like?

Shape of molecule assumes a bent/angular conformation (bond angle = 120°)

 VSEPR for 4 electron clouds

Example: CH4

(1) Draw a dot structure to show the valence electrons

(2) Count the number of “electron clouds” (regions of electron density)

surrounding the central atom

4 electron clouds

(3) Predict the geometry of the electron clouds around the central atom

Since there are 4 electron clouds, these clouds will be furthest away from each
other if they point towards the corners of a tetrahedron:

(4) Ignore any lone pairs and predict the geometry of the molecule/ion

Since we have no lone pairs, the geometry of the molecule/ion is the same as
the geometry of the electron clouds, so the molecule assumes a tetrahedral
conformation (bond angle = 109.5°)

Example: NH3
(1) Draw a dot structure to show the valence electrons

(2) Count the number of “electron clouds” (regions of electron density)

surrounding the central atom

4 electron clouds.

(3) Predict the geometry of the electron clouds around the central atom

Tetrahedron

(4) Ignore any lone pairs and predict the geometry of the molecule/ion

If you ignore the lone pairs and pretend they aren’t there, what does the actual
molecule/ion look like?

Molecule assumes a trigonal pyramidal conformation (bond angle = 107°)

Why a different bond angle? Because lone-pair electrons repel just a little more.

Example: H2O
(1) Draw a dot structure to show the valence electrons

(2) Count the number of “electron clouds” (regions of electron density)

surrounding the central atom

4 electron clouds.

(3) Predict the geometry of the electron clouds around the central atom

Tetrahedron

(4) Ignore any lone pairs and predict the geometry of the molecule/ion

If you ignore the lone pairs and pretend they aren’t there, what does the actual
molecule/ion look like?

Molecule assumes a bent/angular conformation (bond angle = 104.5°)

Why a different bond angle? Because lone-pair electrons repel just a little more,
and in case we have two sets of lone-pair electrons that are repelling, forcing
the two H just a little closer together and thus reducing the bond angle.
 VSEPR for 5 electron clouds
Example: PCl5

(1) Draw a dot structure to show the valence electrons

(2) Count the number of “electron clouds” (regions of electron density)

surrounding the central atom

5 electron clouds.

(3) Predict the geometry of the electron clouds around the central atom

Clouds get furthest away from each other by having 3 along one plane
(equatorial positions), and one pointing up and out and the other pointing down
and out of the plane (axial positions) – trigonal bipyramidal (think of two of the
pyramid-like tetrahedron shapes coming together by their bases):

(4) Ignore any lone pairs and predict the geometry of the molecule/ion
Molecule assumes a trigonal bipyramidal conformation (three different bond
angles, see diagram above.
 Example: SF4

(1) Draw a dot structure to show the valence electrons

(2) Count the number of “electron clouds” (regions of electron density)

surrounding the central atom

5 electron clouds

(3) Predict the geometry of the electron clouds around the central atom

Lone-pair of electrons could either go in the equatorial position (left) or in the axial
position (right). Recall: lone-pairs take up more space and therefore repel a little
more. Since the lone pair in the equatorial position (left) is only 90 from two of the
fluorines, but the lone-pair in the axial position (right) is 90 away from three
fluorines, we are much more likely to see the equatorial set-up (left)

So, the following is what we would likely see:

(4) Ignore any lone pairs and predict the geometry of the molecule/ion

Ignoring the lone-pairs, we see that the molecule assumes a see-saw shape

The naming becomes clear if you flip the shape we drew immediately above:
 Example: CiF3

(1) Draw a dot structure to show the valence electrons

(2) Count the number of “electron clouds” (regions of electron density)

surrounding the central atom

5 electron clouds.

(3) Predict the geometry of the electron clouds around the central atom

Trigonal bipyramidal (with lone pairs in the equatorial position to minimize repulsion)

(4) Ignore any lone pairs and predict the geometry of the molecule/ion

Redraw and put two of the F axial, and then add the single equatorial F.

Molecule assumes a T-shaped conformation (bond angles = 90° and 180°)

 Example: I3–

(1) Draw a dot structure to show the valence electrons

(2) Count the number of “electron clouds” (regions of electron density)

surrounding the central atom

5 electron clouds.

(3) Predict the geometry of the electron clouds around the central atom

Trigonal bipyramidal (with lone pairs in the equatorial position to minimize repulsion)

(4) Ignore any lone pairs and predict the geometry of the molecule/ion

Molecule assumes a linear conformation (bond angle = 180°)

 Example: SF6

(1) Draw a dot structure to show the valence electrons

(2) Count the number of “electron clouds” (regions of electron density)
surrounding the central atom

6 electron clouds.

(3) Predict the geometry of the electron clouds around the central atom

Octahedral (two square-based pyramids with their bases touching)

All 6 positions are equivalent (identical),

meaning there are no equatorial or axial positions.

(4) Ignore any lone pairs and predict the geometry of the molecule/ion

Since there are no lone pairs to consider, the molecule also assumes an
octahedral conformation (bond angle = 90° and 180°)

Example: BrF5
(1) Draw a dot structure to show the valence electrons
(2) Count the number of “electron clouds” (regions of electron density)
surrounding the central atom

6 electron clouds.

(3) Predict the geometry of the electron clouds around the central atom

Since all 6 positions of the octahedron are identical, it doesn’t matter which
position the lone pairs go in

(4) Ignore any lone pairs and predict the geometry of the molecule/ion

Molecule assumes a square pyramidal conformation (bond angle = 90°)

 Example: XeF4

(1) Draw a dot structure to show the valence electrons

(2) Count the number of “electron clouds” (regions of electron density)
surrounding the central atom

6 electron clouds.

(3) Predict the geometry of the electron clouds around the central atom

Lone pairs are most repulsive, so the lone pair of electrons go as far away from
each other as possible

(4) Ignore any lone pairs and predict the geometry of the molecule/ion

Molecule assumes a square planar conformation (bond angle = 90°)

see-saw
Stereochemistry

Structural isomers (constitutional isomers)

Isomer – ‘same parts’

STRUCTURAL ISOMERS – same molecular formula, different connectivities

• Also known as constitutional isomers

e.g.

e.g.
 Chirality

STERIOISOMERS – isomers that differ in their 3D arrangement of atoms

CHIRALITY – an object and its mirror image are non-superimposable, meaning that when the mirror
image of the object is placed over the original object, they do not overlap.

Chiral – objects are not superimposable on their mirror images (but are optically active)

Achiral – objects are superimposable on their mirror images (but are not optically active)
e.g. mirror image of a coffee mug can be superimposed through simple rotation of the coffee mug

Most biological compounds are chiral (i.e. non-superimposable):

ENANTIOMERS (aka optical isomers):
• Greek for ‘opposites’
• Definition – a pair of stereoisomers that are non-superimposable mirror images, and have
opposite configurations at all chirality centers

• Enantiomers have the same physical properties (e.g. melting point, boiling point, density),
but differ in their optical activity (i.e. the direction in which they rotate plane polarized light)
o Enantiomers rotate plane polarized light to an equal but opposite degree
▪ Carvone example (specific to this example, but note that S/R don’t alight with
CCW or CCW or dexo/rotary):
• (S)-carvone rotates plane-polarized light by 10° in one direction
• (R)-carvone rotates plane-polarized light by 10° in the opposite dir.
o Dextro-rotary isomer (Positive/CW direction or rotation)
o Levo-rotatory isomer (Negative/CCW direction of rotation)

OPTICAL ACTIVITY:
Plane polarized light – oscillations of light oriented in a single direction, as created by passing non-
polarized light through a polarizing filter (a filter than only allows light of a specific orientation
through)

(unpolarized light) filter

When a beam of plane-polarized light passes through a chiral molecule (e.g. passed through a
polarimeter tube containing the chiral molecule dissolved in solution), it interacts with the chiral
molecule in such a way that the angle of the plane of oscillation rotates:
 Polarimeter:

Unpolarized light put through a filter to polarize the light.

Polarized light enters a polarimeter tube and hits a solution containing the chiral molecules, which
rotates the polarized light.

The analyzer is rotated by some angle, α, until it matches the new direction of the rotated light.

α is dependent not only on the molecule itself, but also on the concentration of the chiral molecule
(c), and the length of the tube (l):
• [α]Tλ = α / c⋅l
o Specific rotation, [α]Tλ
▪ Specific to a particular chiral molecule at a particular temperature (T in
superscript) and wavelength (λ in subscript)
o Observed rotation (α)
o Concentration (c)
o Length of tube (l)
ENANTIOMERS (from above)
• A pair of stereoisomers that are non-superimposable, mirror images, and have opposite
configurations at all chirality centers

DIASTEREOMERS
• A pair of stereoisomers that are non-superimposable, non-mirror images, and have opposite
configurations at some but not all chirality centers
o i.e. stereoisomers of a compound that are not enantiomers to each other

Enantiomers Diastereomers
I and II I and III
III and IV I and IV
II and IV
Identifying the chiral carbon center:

CIRAL CENTER – a tetrahedral (sp3 hybridized) carbon atom that has 4 different groups attached,
each of which are placed at the corners of the tetrahedron (i.e. a triangle-based pyramid)
• 2n = Maximum potential number of stereoisomers, where n = number of chiral centers

Compound 1 has a chiral carbon center, because it is attached to four different groups (W, X,
Y, and Z). Compound 2 is a mirror image of Compound 1.

If the molecule is chiral, compounds 1 and 2 should be non-superimposable.

• To confirm this, rotate compound 1 around one axis of rotation, and see if any of the
products of rotation lead to compound 2. If not, then compound 1 is chiral.

Since none of the above structures is the same as the mirror image (i.e. compound 2), we can
conclude that compound 1 is chiral.
––––––

NOTE: the 4 substituents that are attached must be different from each other:
 The Cahn-Ingold-Prelog rules for assigning ‘R and S’ configuration to chiral centers:

Allows us to systematically assign a name to the configuration of each chiral carbon of the two
enantiomers.

NOTE: There is no correlation between the optical activity (i.e. positive/CW and negative/CCW) and
the R & S stereochemical labels.

Spatial arrangement of a tetrahedral carbon:

(1) Prioritize the four groups attached to the chiral center (based on atomic number)
• The higher the atomic number, the higher the priority.

If the atoms that are directly attached to the carbon center have the same rank, proceed along the
two substituent chains until you find a point of difference. Treat double bonds as if there are two
separate bonds, each with that atom at the end of it.

e.g. O > C > H in terms of priority (given by their atomic numbers), so priority is assigned as such:
(2) Orient the groups so that the LOWEST priority group (#4) is pointing away (i.e. hashed
wedge position)
o If the lowest priority group is already pointing away, you’re good to go.

o If the lowest priority group is pointing towards you, a trick/shortcut that you can use is
just to proceed with step 3, but then SWITCH whatever answer you get.
Example:

“Looks like” (R), but lowest priority group is pointing towards us, to molecule is actually (S)

o If the lowest priority group is in a position that is flat with the plane (i.e. not coming
out of the page and not going into the page), you’ll need to visualize that you are
looking down the bond that leads to the lower priority group, and redraw the
molecule with what you ‘see’.

(3) Draw a curved arrow from the highest priority substituent (#1) to the second lowest priority
substituent (#3)
o (S) label – given if arrow turns in a CCW direction
o (R) label – given if the arrow turns in a CW direction

–––
Chirality and drug development
• Chirality is extremely important in drug development and pharmaceutical industries.
• A large proportion of drugs are either chiral, or racemic mixtures (i.e. an equal mixture of the
two enantiomers)
• Surprisingly, biological systems can recognize the two enantiomers as two very different
substances.
• Enantiomers of chiral drugs differ in their interactions with enzymes, proteins, receptors, and
other chiral molecules (e.g. chiral catalyst), leading to differences in the biological activities of
the two enantiomers (e.g. pharmacology, toxicity, pharmacokinetics, metabolism, immune
response, etc.)
o Thus, when chiral drugs are synthesized, a substantial amount of effort goes towards
the separation of the two enantiomers
o This ensures that only the biologically active enantiomer is present in the final drug.

Why do enantiomers have different biological activities?

• Recognition of chiral drugs by specific receptors is explained by a three-point interaction of
the drug with the receptor site – only a particular enantiomer that has a complementary
shape to the receptor site can fit into said site.

Since the enantiomer on the right cannot interact with the receptor,
there is no active response, and thus the enantiomer is inactive.

The attachment of an enantiomer to the chiral receptor is analogous to a hand fitting into a glove – a
right glove only fits a right hand, and no matter how you rotate the left hand, it won’t fit in the right
glove.

–––
Enantiomeric excess (ee) – a measurement of the degree of purity of any chiral sample (i.e. the
degree to which a sample contains one enantiomer in excess over the other).

• Racemic mixture ee = 0% both enantiomers (S and R) are present in a 1:1 ratio

• Pure enantiomer ee = 100% only R isomer, or only S isomer is present

• 70% R, 30% S ee = 40% this can be rationalized as a mixture of 40% pure R

with 60% (30% R and 30% S) of a racemic mixture.

Example of chiral drugs whose enantiomers vary drastically in their properties:

1) Thalidomide

Causes teratogenic birth defects (fetus Effective sedative, soothing effect, relieves
has deficient, redundant, misplaced, or anxiety, induces drowsiness
grossly misshapen body parts)

S-Thalidomide was responsible for over

2000 causes of serious birth defects in
children born to women who took the
racemic mixture during pregnancy

2) Carvone

Since the human olfactory sensory organs are chiral, S-carvone smells like caraway seeds while
R-carvone smells like spearmint leaves.

3) Ibuprofen

S-Ibuprofen has the desired pharmacological activity, while R-ibuprofen is totally inactive.
 Cis-trans isomerism

Cis/trans terminology requires that we have two identical groups to compare

trans isomer – Identical groups are on opposite sides of the double bond
cis isomer – Identical groups on the same side of the double bond

E-Z isomerism

E-Z system allows us to assign a configuration name when the four groups surrounding the double
bond are non-identical – more inclusive than the cis-trans system.

Assign priorities (higher atomic number = higher priority) to the groups to the left of the bond, and
separately to the groups on the right of the bond.
E isomer – Like-priority groups are on opposite sides of the double bond
Z isomer – Like-priority groups on the same side of the double bond

Examples:

Mnemonic for cis/trans and E/Z:

e-trans.fer (group transferred to other side – opposite)
cis ze zame zide (‘sss’ and ‘zzz’ sound – same)
 Conformations of ethane

KEY:
VIEWS
CONFORMATIONS – different arrangements of atoms that result from bond rotation

Wedge and dash view

Staggered Eclipsed

Sawhorse representation

Staggered Eclipsed

Newman projection (‘looking down the carbon-carbon bond’)

• Front carbon is represented by the vertex of the three lines
• Back carbon is represented by the large, outer circle

Staggered Eclipsed

Dihedral angle (aka torsional angle) – the angel between planes through two sets of three
atoms
 Conformational analysis of butane

Potential
energy

Eclipse type Potential energy

H-H eclipse: 4 kJ/mol
H-CH3 eclipse: 6 kJ/mol
CH3-CH3 eclipse: 11 kJ/mol

The most stable form of the molecule has the lowest potential energy (which is the anti
conformation)

Potential
energy

Gauche conformation is a little higher in energy than the anti conformation, since the two methyl
groups are closer together in space, which has a destabilizing effect.
Covalent Bonds

VEs, Octet Rule, Ionic bonding, Covalent bonding

(mostly from KA text-based resource)

Octet rule – Most atoms ‘want’ 8 valence electrons (VE, i.e. electrons in the outermost shell of an
atom).
• Exceptions:
o Hydrogen (H) and helium (He) have a single electron shell which accommodates only 2
electrons (thus follow the duet rule)
o Boron (B) can only accommodate 6 VEs
▪ This results in some anomalous properties for boron compounds because they
are “short of electrons”.
▪ This shows that covalent bonding between non-metals can occur to form
compounds with less than an octet on each atom.
• However, in general, achieving the octet configuration is the driving force for chemical
bonding between atoms.
Ionic bonding – a bond between two ions (i.e. carrying a charge) via a donation of VE that helps
both the donor and the recipient atom reach an octet configuration. ΔEN > 1.7

Covalent bonding – neither atom parts with their VE, but instead they share VE

• NON-POLAR covalent bonding

o Covalent bond where electrons are shared EQUALLY between two atoms (e.g. Cl-Cl
example above)

• POLAR covalent bonding

o Covalent bond where electrons are shared UNEQUALLY between two atoms, and
there is a net dipole moment (see next lecture)
o Arises when there are moderate differences in ELECTRONEGATIVITY (the power of an
atom in a molecule to attract electrons to itself)
▪ Trend of electronegativity goes from bottom left (least electronegative) to top
right (most electronegative) of the periodic table (ignoring H and He)
o The more electronegative atom will pull the shared electron towards itself more.

The atom that has the greater share of the bonding electrons bears a partial negative charge (δ–),
and the other atom automatically bears a partial positive charge (δ+) of equal magnitude.
This explains why water, H2O, is a polar molecule with partial charges – oxygen is more
electronegative and therefore ‘hogs’ the electrons, giving it a partial negative charge:

Non-polar covalent bonds Polar covalent bonds

Often occurs between like atoms Always occurs between different atoms

Electronegative difference between bonded Electronegativity difference between bonded

atoms is small (<0.5 Pauling units) atom is moderate (0.5-1.7 Pauling units)
e.g. C-H bonds e.g. O-H bonds
(2.55 of Carbon minus 2.1 of e.g. O-C bonds
Hydrogen equals 0.45).
Electrons are shared equally between atoms Electrons are not shared equally between atoms

Single and multiple covalent bonds

The number of pairs of electrons shared between two atoms determines the type of
covalent bond formed between them:
–––––––––––––––––––––Single bond example–––––––––––––––––––––

–––––––––––––––––––––Double bond example–––––––––––––––––––––

–––––––––––––––––––––Triple bond example–––––––––––––––––––––

 Dipole moment

Dipole moment – arises when atoms in a molecule share electrons unequally (i.e. a polar molecular)
with a net direction.

Dipole moment (μ) = Qd

• Magnitude of charge (Q)
• Distance between proton and electron (d)

The math and equation are not important, the concept of the dipole moment and what makes a
polar molecule is.

Examples:

CO2
• μ = 0, since the magnitude of charge of the individual bond dipoles
cancel each other out.
• Thus, even though the bonds have polarity, CO2 is a non-polar molecule.

H 2O
• There is a net dipole moment (μ) in one direction, due to the individual
bond dipoles adding to give a molecular dipole
• Thus, there is a dipole moment associated with H2O, making it a polar
molecule.

CCl4
• μ = 0, since the magnitude of charge of the individual bond dipoles
cancel each other out.
• Thus, CCl4 is a non-polar molecule.

CHCl4
• There is a net dipole moment (μ) in one direction, due to the individual
bond dipoles adding to give a molecular dipole
• Thus, there is a dipole moment associated with CHCl4, making it a polar
molecule.
 Intramolecular and intermolecular forces

Two kinds of attractive forces that operate in a molecule:

(1) Intramolecular forces – the forces that hold atoms together within a molecule.
• Strong attractive force
• Analogy – towels stitched together
• Different types of intramolecular forces:

o 1 | Covalent bonds
▪ Sharing of VEs

▪ 1a | Non-polar (ΔEN = <0.5)

• FORCE BETWEEN NUCLEI AND SHARED ELECTRONS
• e.g. CH4

▪ 1b | Polar (ΔEN = 0.5-1.9)

• FORCE BETWEEN PARTIALLY CHARGED CATION AND PARTIALLY CHARGED ANION
• e.g. H2O

o 2 | Ionic bonds
▪ FORCE BETWEEN CATIONS AND ANIONS

▪ Complete transfer of VEs

▪ e.g. Na+ –Cl

o 3 | Metallic bonds
▪ FORCE BETWEEN METAL CATIONS AND DELOCALIZED ELECTRONS
▪ Covalent bonding between atoms of METAL.

▪ The bond is formed via the attraction of mobile

electrons (since VEs are free to move through the
lattice, forming a ‘sea of electrons’) to the fixed
positively charged metal ions
• e.g. samples of pure elemental metals (e.g.
gold, aluminum) or alloys (e.g. brass, bronze)

▪ It is the free moving (mobile) VE in metals that are responsible for their ability
to effectively conduct heat and electricity, and their reflective properties
(free moving electrons oscillate and give off photons of visible light)
(2) Intermolecular forces – the forces that exist between molecules
• Much weaker, more of an association
• Analogy – stitched towels joined to other stitched towels by Velcro
• Determine the physical properties of molecules such as their boiling point, melting point,
density, enthalpy of fusion, enthalpy of vaporization.

• Different types of intramolecular forces:

o 1 | London dispersion forces (a type of VdW force)
▪ INTERACTIONS BETWEEN TEMPORARY DIPOLES FORMED DUE TO THE
TRANSIENT POSITION OF ORBITING ELECTRONS
▪ Exist between all types of molecules (regardless of if they
are intramolecular forces are ionic, polar covalent, or
non-polar covalent)
▪ Weakest of the intermolecular forces
• Thus, breaking of these forces doesn’t require much energy
• This helps explain the low freezing temperatures of compounds that
only have London dispersion forces of attraction between the
molecules (i.e. nonpolar covalent compounds such as CH4, O2, N2).
▪ The more electrons a molecule has, the stronger the London dispersion force
are.
• e.g. Br2 has more electrons that Cl2, so Br2 has stronger London
dispersion forces, resulting in a higher boiling point (59 °C compared to
–35 °C)

o 2 | Dipole-dipole interactions
▪ Occur when the PARTIALLY POSITIVE CHARGED PART (δ+) of a
dipole molecule interacts with the PARTIALLY NEGATIVE
CHARGED PART (δ–) of the neighboring dipole molecule.
▪ Requires partially charged ions (polar covalent molecules)

––> Hydrogen bonding

▪ The strongest form of dipole-dipole interaction
▪ Occurs specifically between AN H ATOM (which has a partially
positive end) AND AN F, O, OR N ATOM (which have partially
negative ends)
• Mnemonic: “Hydrogen just wants to have FON”
▪ Play an important role in biology (e.g. holding nucleotide bases together in
DNA and RNA)
▪ Hydrogen bonding is a relatively strong force that requires considerable energy
to break.
• This explains the exceptionally high boiling and melting points of
compounds like water (H2O) and hydrogen fluoride (HF)
Intermolecular forces of molecules – examples:

––––––––––––––––––––––––––––––––

––––––––––––––––––––––––––––––––
Forces of attraction and their effect on the PROPERTIES of compounds:

Nonpolar covalent compounds (e.g. CH4, N2) only have London dispersion forces between molecules.

Polar covalent compounds (e.g. HCl, HI) have both dipole-dipole interactions between partially
charged ions and London dispersion forces between molecules.

The stronger the intermolecular forces of attraction, the more energy that is required to break those
forces.

This means that ionic compounds and polar covalent compounds have higher boiling points, higher
melting points, higher enthalpy of fusion, and higher vaporization compared to non-polar covalent
compounds.

Relative order of boiling and melting points:

Applying this to common compounds:

• Methane (CH4) is a gas at room temperature, meaning that it’s boiling point is below room
temperature (it’s actually as low as –161.5 °C). This is because methane is a nonpolar covalent
molecule, and thus the only intermolecular forces acting are London dispersion forces, which
are weak and do not require much energy to break.

• An intermediate example would be water (H2O), which boils (becomes a gas) at 100 °C, since
it is a polar covalent compound that exhibits hydrogen bonding (as well as the London
dispersion forces, by default). Thus, the intermolecular forces require more energy to break.

• On the extreme end, salt (NaCl) has a boiling point of 1413 °C, which makes sense since it is
an ionic compound, which exhibit strong ion-to-ion attraction between ions (as well as
London dispersion forces, by default), and thus requires a huge amount of energy to break
these intermolecular forces.
 Electron configuration (from Bozeman Science)

Electron configuration – the distribution of electrons (both core and valence) in atoms or ions,
organized into shells (1 to 7), subshells (s, p, d, & f), and orbitals (2 electrons per orbital).
• Core electrons – inner shells
• Valence electrons – outermost shell
o e.g. 3 electrons in shell 2 for Boron means that boron has 3 VEs

Subshell Number of orbitals Maximum number of electrons (2 electrons per orbital)

s 1 2
p 3 6
d 5 10
f 7 14

Energy increases along the arrow trend.

Assigning electron configuration

Use the atomic number to find the total number of electrons (& adjust accordingly if molecule
happens to have a net charge), and fill the orbitals sequentially following the arrows (e.g. you’d fill
4s before 3d)

Atom Number of electrons Electron configuration

H 1 1s1
B 5 1s2 2s2 2p1
Ne 10 1s2 2s2 2p6
Na 11 1s2 2s2 2p6 3s1
Since the electron configurations get long, [Ne] 3s1
long abbreviate using the noble gases:
 sp3 hybridization

CH4 example:
• The four C-H bonds of CH4 are equivalent in terms of bond length, energy, etc.
• However, when we draw the energy diagram for the orbitals, it looks like the following (VEs
circled in green):

• This electron configuration implies that carbon would only form two bonds, because there
are only two unpaired electrons (not four, as required for four bonds), and that there is an
energy mismatch.
• However, we know that there are four equivalent bonds made in a CH4 molecule.

This can be explained by sp3 hybridization

• The 2s orbital moves up in energy and the three 3p orbitals move down in energy to form
four new hybrid sp3 orbitals (circled in cyan), each of which has one unpaired electron.
o These sp3 hybrid orbitals have 25% S orbital character and 75% P orbital character.

• We now have four unpaired electrons (capable of producing 4 different bonds) of equal
energy
Shape of sp3 hybrid orbitals
• s orbitals – sphere
• p orbitals – dumbbell, or ‘infinity loop shape’
• sp3 orbital – large frontal lobe, small back lobe

s p sp3

Drawing the orbitals in molecules (continuing the CH4 example)

Carbon surrounded by its four sp3 hybrid orbitals (draw without the small back lobe for simplicity),
each with one electron in (drawn as a dot)

Hydrogens surrounded by their singular s orbital each containing a singular electron.

The orbitals overlap and the unpaired electrons from each atom forms an electron pair.

Head-on overlaps like this form a single covalent bond, also known as a sigma (σ) bond.
Example 2: C2H6

Now we have a situation where two sp3 hybrid orbitals (one from each C) are overlapping. This is
also a head-on overlap, so this is also a sigma (σ) bond.

Rotation:
• Sigma (σ) bonds allow for free rotation around the bond
• This allows different conformations of the molecule to form (e.g. staggered vs. eclipsed).

Bond length:
• Bond length of the single bond between two carbons (e.g. CH4): 1.54 Å

Geometry
• Atoms with a sp3 hybrdization state assume a tetrahedral shape (if there are no surrounding
lone electron pairs)
 sp2 hybridized orbitals

C2H4:

Since the carbons are only bonded to three atoms, there are only 3 hybrid orbitals required, and thus
we must need a different hybridization than sp3.

This leads us to sp2 hybridization, where we only take 2/3 of the 2p orbitals and form a hybrid with
the 2s orbital, leaving the final 2p orbital unhybridized.

sp2 hybrid orbitals have 33% S character and 67% P character

• Thus, there is more S character in an sp2 hybrid than in an sp3 hybrid, and since the electron
density in an S orbital is closer to the nucleus, the frontal lobe is a little bit shorter, which
influences bond length.

Shape of sp2 hybrid orbitals

• s orbitals – sphere
• p orbitals – dumbbell, or ‘infinity loop shape’
• sp2 orbital – large frontal lobe, small back lobe

s p sp2
Drawing the orbitals in molecules (continuing the C2H4 example)

Carbon surrounded by its three sp2 hybrid orbitals (draw without the small back lobe for simplicity),
and one unhybridized ‘p’ orbital. Each orbital has one electron in (drawn as a dot)

Draw in the second C and its four total orbitals (three ‘sp2’ hybridized, one ‘p’ unhybridized)

Add in the hydrogens with their unhybridized ‘s’ orbitals.

Count up the sigma (σ) bonds (head on overlap of orbitals)

The unhybridized ‘p’ orbitals also overlap (in a side-by-side fashion), creating a pi (π) bond

When we see a double bond in our dot structure, one of those bonds is a bond sigma (σ) bond, and
the other is a pi (π) bond.

Rotation:
• π bonds DO NOT ALLOW FOR FREE ROTATION

Bond length:
• Recall: Bond length of the single bond between two carbons (e.g. CH4): 1.54 Å
• New: Bond length of the double bond between two carbons (e.g. C2H4): 1.34 Å

• Thus, double bonds are shorter than single bonds.

o This is because sp2 hybrid orbitals have more ‘s’ character than sp3 hybrid orbitals
o This means that electron density is closer to the nucleus, which makes the lobe a little
shorter than before, and consequently the distance between the two carbons is
decreased

Geometry:
• Atoms with a sp2 hybrdization state assume a trigonal planar shape (if there are no
surrounding lone electron pairs)
 sp hybridized orbitals

Example: C2H2

Since the carbons are only bonded to two atoms, there are only 2 hybrid orbitals required.

This leads us to sp hybridization, where we only take 1/3 of the 2p orbitals and form a hybrid with
the 2s orbital, leaving the other two 2p orbitals unhybridized.

sp hybrid orbitals have 50% S character and 50% P character

• Thus, there is more S character in an sp hybrid than in an sp2 hybrid, and since the electron
density in an S orbital is closer to the nucleus, the frontal lobe is even shorter, which further
influences bond length to be even shorter.

Shape of sp hybrid orbitals

• s orbitals – sphere
• p orbitals – dumbbell, or ‘infinity loop shape’
• sp orbital – large frontal lobe, small back lobe

s p sp
Drawing the orbitals in molecules (continuing the C2H2 example)

Carbon surrounded by its two sp2 hybrid orbitals (draw without the small back lobe for simplicity),
and two unhybridized ‘p’ orbitals. Each orbital has one electron in (drawn as a dot)

Draw in the second C and its four total orbitals (two ‘sp’ hybridized, two ‘p’ unhybridized)

Add in the hydrogens with their unhybridized ‘s’ orbitals.

Count up the sigma (σ) bonds (head on overlap of orbitals)

The two sets of unhybridized ‘p’ orbitals also overlap (in a side-by-side fashion), creating TWO pi (π)
bond

When we see a triple bond in our dot structure, one of those bonds is a bond sigma (σ) bond, and the
other two are pi (π) bonds

Rotation:
• π bonds DO NOT ALLOW FOR FREE ROTATION, so just like double bonds, triple bonds do not
allow rotation either.

Bond length:
• Recall: Bond length of the single bond between two carbons (e.g. CH4): 1.54 Å
• Recall: Bond length of the double bond between two carbons (e.g. C2H4): 1.34 Å
• New: Bond length of the triple bond between two carbons (e.g. C2H2): 1.20 Å
•

• Thus, triple bonds are shorter than double bonds (which are shorter than single bonds).
o This is because sp hybrid orbitals have more ‘s’ character than sp2 hybrid orbitals,
which have more ‘s’ character than sp3 hybrid orbitals.
o This means that electron density is EVEN closer to the nucleus, which makes the lobe a
EVEN shorter than before, and consequently the distance between the two carbons is
decreased

Geometry
• Atoms with a sp3 hybrdization state assume a linear shape (if there are no surrounding lone
electron pairs)

Increasing s character (sp > sp2 > sp3 in terms of s character) corresponds to shortening bond length.
 Steric number (sp3 examples)

Steric number (SN) = # σ bonds (around central atom) + # lone pairs of electrons (around central atom)

The steric number (SN) tells us how many hybridized orbitals we need

Example: CH4

Since sp3 hybridization gives us 4 hybrid orbitals, we know that the orbitals of C must be sp3
hybridized.
––––––
Example: NH3

Since sp3 hybridization gives us 4 hybrid orbitals, we know that the orbitals of N must be sp3
hybridized.

––––––
Example: H2O

Since sp3 hybridization gives us 4 hybrid orbitals, we know that the orbitals of O must be sp3
hybridized.
 Steric number (sp2 examples)

Steric number (SN) = # σ bonds (around central atom) + # lone pairs of electrons (around central atom)

The steric number (SN) tells us how many hybridized orbitals we need

Example: C2H4

Recall: only one of the bonds in a double bond is a sigma (σ) bond.

Since sp2 hybridization gives us 3 hybrid orbitals, we know that three of the orbitals of C must be sp2
hybridized orbitals (with the other orbital being unhybridized ‘p’ orbital).

In this case, the unhybridized ‘p’ orbital contains an electron, and forming a pi (π) bond with the
neighboring carbon (which in the same situation)

Example: BF3

Since sp2 hybridization gives us 3 hybrid orbitals, we know that three of the orbitals of C must be sp2
hybridized orbitals (with the other orbital being unhybridized ‘p’ orbital).

In this case, since boron (B) only has 3 VE (which are distributed to the three sp 2 hybridized orbitals),
the unhybridized ‘p’ orbital doesn’t contain any electrons. This means that boron can accept a pair of
electrons, and function as a Lewis Acid.
 Steric number (sp examples)

Steric number (SN) = # σ bonds (around central atom) + # lone pairs of electrons (around central atom)

The steric number (SN) tells us how many hybridized orbitals we need

Example: C2H4

Since sp hybridization gives us 2 hybrid orbitals, we know that two of the orbitals of C must be sp
hybridized orbitals (with the other two being unhybridized ‘p’ orbitals).

Example: CO2

Since sp hybridization gives us 2 hybrid orbitals, we know that two of the orbitals of C must be sp
hybridized orbitals (with the other two being unhybridized ‘p’ orbitals).
 Organic hybridization practice

Example 1 –> Identify the hybridization states and predict the geometries for all atoms (except H) in
the following molecule, and count the total number of sigma (σ) and pi (π) bonds

We can identify the hybridization states and predict the geometries of the carbons simply by
identifying single, double, and triple bonds:

Alternatively, steric number (SN) could have been used to identify the hybridization states:

Steric number (SN) = # σ bonds (around central atom) + # lone pairs of electrons (around central atom)
Total number of sigma (σ) and pi (π) bonds can simply be counted

––––––
Example 2 –> Identify the hybridization states and predict the geometries for all atoms (except H) in
the following molecule, and count the total number of sigma (σ) and pi (π) bonds

For the oxygen, steric number (SN) is probably the easiest approach, since there are lone electron
pairs involved now.

Since you ignore lone-pair electrons when considering the geometry, we can say that oxygen is bent.
Example 3 –> Identify the hybridization states and predict the geometries for all atoms (except H and
O) in the following molecule, and count the total number of sigma (σ) and pi (π) bonds

Simplest approach is just counting bonds for carbons, and SN for the nitrogen

Since you ignore lone-pair electrons when considering the geometry, we can say that nitrogen is
trigonal pyramidal
Separations and Purifications

Simple and fractional distillations

Distillation is used to separate and purify chemicals based on their respective boiling points. The
process uses a series of vaporizations and condensations.

––– Simple distillation –––

Equipment:
• Oil bath – oil doesn’t evaporate when you heat it, so it is used to keep a constant
temperature throughout the process.
• Distilling flask – contains the mix of compounds to be separated
• Thermometer – used to measure what temperature your compounds are boiling out at.
• Condenser – kept cool by water cycling in and out. The cool temperature allows vaporized
compounds to condense back into a liquid phase.
• Vacuum adaptor – allows the pressure of the entire system to be lowered, making it easier to
vaporize substances.
• Receiving flask – collects the condensed liquid.
• Ice bath – keeps the receiving flask cold so that the liquid can readily condense back into its
pure form.

Process:
• Liquid in distilling flask gets heated to its boiling point, at which it vaporizes to gas.
• As a gas, it travels up and enters the condenser, whereby the cool temperature causes it to
condense back down to a liquid.
• The liquid now collects in the cool receiving flask.
• Receiving flask is switched out for each compound present (or else you’ll just end up with a
mixture like you started with)
Example 1:

Important concept:
• During a phase change (liquid -> gas), the temperature remains constant
• This is represented by a plateau on the graph

Example 2:
• Distillation can be used to increase the concentration of ethanol (think: ‘triple distilled
vodka’).
• Why distill multiple times?
o Ethanol (BP = 78 °C) and water (BP = 100 °C) have similar BPs, so the distilling process
is not as clear cut as the process we saw above.
o Instead of producing nice steep lines followed by nice flat lines, etc., you get a curve
that looks like the graph below, meaning that the water and ethanol are not
completely separated.

• Distilling multiple times helps drive the curve towards our ideal clear-cut lines, and thus helps
with the process of separating ethanol from water.
• However, this is time consuming, and so fractional distillation can be used instead, whereby
multiple distillations are performed at once (see below)
 ––– Fractional distillation –––
• Same set up as simple distillation, but now a fractionating column is added.
• The fractionating column contains beads (or something of that nature)
• After vaporizing for the first time, the compound will condense on one of the beads, and from
there it will vaporize again, and condense onto another bead, etc.
• The compound undergoes a number of vaporization-condensation cycles before it eventually
reaches the final condenser precluding its collection.
• This multiple distillation process makes for a much purer final collection.

Simple distillation – used when compounds have BPs that are 25-30 °C or more apart.

Fractional distillation – used when compounds have BPs within a range of 25-30°C of each other.
 Acid-base Extractions
Chemicals can also be separated by acid-base extractions

Equipment:
• Separatory funnel (aka sep funnel) – has an opening from which you can pour in liquid
• Stop cock – prevents liquid from freely leaving the separatory funnel
• Flask – collects liquids

Process:
• Pour in a mixture of liquids, shake the separatory funnel, and allow it to settle.
• The components have different densities, meaning that they will layer out, with the higher
density components being at the bottom, and the lower density components being at the top
of the funnel.
o Organic phase – lower density (upper layer)
▪ Contains neutral (uncharged) compounds
o Aqueous phase – higher density (lower layer)
▪ Contains water and charged ions
• Open the stopcock and allow aqueous phase to flow into the flask.
• Once you’ve collected all of the aqueous phase in the flask, stopcock is closed.
Example 1 (neutral compound + basic compound):
• Hexane (left) and propanamine (right).
• To get one of the compounds into the organic layer and the other into the aqueous layer, we
want to turn one of the compounds into an ion (such that it will go into the aqueous phase)
while leaving the other compound uncharged (such that it will go into the organic phase).
• Since hexane is neutral and propanamine is basic (due to its amino group), we want to add
something that will react with the basic propanamine.
• What reacts with a base? A strong acid – the additional of HCl leads to a reaction whereby the
nitrogen of propanamine deprotonates the HCl, producing a compound with a charged amino
group (and of course Cl– anions)

Example 2 (neutral compound + slightly acidic compound)

• Same idea as above, but now adding a strong base (e.g. NaOH)
• Electrons of the strong base deprotonate the phenol group of the acidic compound,
producing an anion that can go into the aqueous phase, while leaving the neutral compound
neutral such that it can go into the organic phase.
Example 3 (neutral + very weak acid + weak acid)
• Hexane (neutral), phenol (very weak acid), acetic acid (weak acid)
• If we used a strong base (NaOH) in this case, both acids with be deprotonated, and thus both
would enter the aqueous phase, preventing their separation.
• Instead, a mild base is used (for example, sodium bicarbonate Na + –HCO3), such that it can
deprotonate weak acids, but can’t deprotonate very weak acids.
• Thus, only the acetic acid (weak acid) gets deprotonated, while the phenol (very weak acid)
remains untouched.
• Aqueous – acetate anion
• Organic – hexane + phenol
o Now, these two can be separated in a second step, just as before (just using NaOH is
fine)

––– Next moving on to large section about chromatography-based separation of compounds ––––
 Chromatography – introduction and common terms

Chromatography – used to separate a mixture of chemical substances into its individual components.
• Multiple types of chromatography (e.g. liquid, gas, ion-exchange, affinity), but all employ the
same basic principles.

Terms:

Stationary phase (adsorbent) is what the analyte gets ‘bound to’. In most case, this is silica gel.

Elution is then the process of removing analytes from the adsorbent.

 Principle of separation of different compounds

• Differential affinities of the various components of the analyte towards the stationary and
mobile phases results in the separation of the components.
• Affinity is dictated by two properties of the molecule:
o Adsorption:
▪ How well a component of the analyte sticks to the stationary phase
▪ Higher adsorption to stationary phase = Slower movement of molecule through
column
o Solubility
▪ How well a component of the analyte dissolves in the mobile phase.
▪ Higher solubility in mobile phase = Faster movement of molecule through
column
• The interplay between a molecule’s adsorption and solubility determines the differential rates
at which the different components of the analyte will move through the column.

• Polarity of the analyte components, the stationary phase, and the mobile phase dictates the
affinities that will occur between analyte components and the phases. Polarity varies
between compounds.
Example:
o Analyte: Protein (A) + Lipid (B)
o Stationary phase: Silica (polar)
o Mobile phase: Hexane (non-polar)
o Since protein (A) is polar in nature, it will adsorb to the polar stationary phase (silica),
and will not dissolve in the non-polar mobile phase (hexane)
o Since lipid (B) is non-polar in nature, it will readily dissolve in the non-polar mobile
phase (hexane) without adhering to the silica, and thus will elute out of the column
with hexane.
o Once lipid (B) is eluted out, the mobile phase will be changed to something polar (e.g.
acetonitrile). By doing this, we will now force protein (A) to detach from the silica and
dissolve in the polar solvent, and get eluted out of the column with the solvent.
Normal- vs. Reverse-phase chromatography
• Normal-phase chromatography – polar stationary phase, non-polar mobile phase.
o Mnemonic – usually, the pole is polar (pole = column, stationary phase)
• Reverse-phase chromatography – non-polar stationary phase, polar mobile phase.

Import concept:
• Polar (hydrophilic) likes other polar molecules.
• Non-polar (hydrophobic) likes other non-polar molecules.
• Polar and non-polar molecules do not ‘get along’ well.
• Important to keep straight from positive and negative charges, which have the opposite
‘rules’

Column chromatography
Equipment:
• Column – has opening at top and contains:
o Silica – stationary phase, fills most of the column.
o Sand layer – provides a level surface on to which the
silica layer can be packed
o Cotton ball layer – prevents silica from running out
with the solvent
• Stopcock – allows chemist to control flow
• Flask – collects the separated compound

Process:

Each flask you collect is called a ‘fraction’

Notes:
• Column must be kept wet with solvent at all times, because if it runs dry it can crack, or cause
mixing of bands.
• Important to load analyte in flat to prevent the formation
of fractions that contain more than one compound:
 Thin layer chromatography (TLC)

Normal phase TLC is performed on a piece of glass that is coated with a thin layer of silica.

Stationary phase: Silica gel coating the glass (polar)

Mobile phase: Solvent in which the plate gets dipped (less polar compared to silica)
Runs up the plate by capillary action

The polar components of the analyte will adhere to the silica and thus travel slowly up the plate.

The less polar or non-polar components will not adhere well to the silica, and thus will travel up the
plate relatively fast with the solvent.

UV

Notes:
• All measurements start from the origin (not the bottom of the plate)
• The measurement for the total distance travelled by the solvent shouldn’t ever measure to the very
top of the plate (since you should never let your solvent run that far).

Retention factor or retardation factor (Rf) – a quantitative parameter, defined as the following:
Rf = distance traveled by the individual component (solute)
total distance travelled by the solvent

Simple rules of (normal phase) TLC:

• Most polar -> least traveled -> lower Rf
• Least polar -> most traveled -> higher Rf

From the experiment above, we can conclude:

• Compound ‘C’ is the most polar of the three (travelled least far, and has an Rf = 1/5 = 0.2)
• Compound ‘B’ is the least polar (travelled furthest, and has an Rf = 3/5 = 0.6)
 Gas chromatography

Gas chromatography separates compounds based on boiling point.

Chromatogram
Intensity (y)

Time (x)

Process:
• Liquid sample is injected, and gets vaporized into gas.
• A stream of already-flowing inert gas (mobile phase) joins the vaporized sample, pushes it
into the ‘column’ (a coiled tube)
• The column walls are coated in a liquid (stationary phase).
• Gases travel through the column at different rates, based on their BPs:
o Compounds with lower BPs are more willing to go into the gas phase, and therefore
better interact with the inert gas (mobile phase), and will thus elute faster
▪ Analogy – low BPs = very willing to go into the gas phase, ‘like’ hanging out
with other gases so will travel with them.
o Compounds with higher BPs are not as willing to go into the gas phase, and therefore
better interact with the liquid (stationary phase), and will thus elute slower
▪ Analogy – high BP = not quite as willing to go into the gas phase, doesn’t like to
hang out with gases, would prefer to hang out with liquids as much as possible
• The detector detects how many of each particle comes out, and displays them as a
chromatogram:
o The solvent (which the compound was dissolved in) usually has a relatively low BP, so
eludes from the column first (and thus makes the first peak on the chromatogram)
o The magnitude of the peak corresponds to the relative amount of the compound in
the original mixture.
o The position of the peak (i.e. at what time that compound eluted from the column)
corresponds to the ID of the compound.
▪ For this ID, the experimental chromatogram is compared to a reference
chromatogram

The size, or molecular weight (MW) of a compound also influences rate of elution from the column:
• Smaller molecules elute quicker (analogy – ‘child getting blown around in the wind’)
• Larger molecules take longer to elute (analogy – ‘sumo wrestler barely pushed by the wind’)

Simple rules of gas chromatography

• Low BP & Lower MW -> Elute faster
• High BP & Higher MW -> Elute slower
 Types of chromatography

First four fall under the category of ‘liquid chromatography’

––––––––

Analogy for size exclusion chromatography – small cars can fit down on all the curved and narrow
back roads (longer route, takes longer), while large transport trucks can only travel on the highway
(shorter route, takes less time)
Anion-exchange
chromatography means
that the resin/beads are
cationic, and anionic
molecules in your analyte
will elute last (only when
you flush with NaCl)

Volatilized = vaporized

Molecules with a lower BP

(i.e. more volatile) are
able to travel through the
column faster
 From the KA video ‘basics of chromatography’.
Essentially describes the same information from the table above.

––– Moving away from chromatography now ––––

 Gel electrophoresis

Gel electrophoresis uses electrical fields to separate DNA or proteins by SIZE.

Equipment:
o GEL
o Agarose
▪ Large pore size // Used for separating out large pieces of DNA (>50 bp)
▪ Mnemonic – agarose sounds like ‘a grows’, grows = large

o SDS-PAGE
▪ Small/fine pore size // Used for separating out small pieces of DNA or proteins
▪ Mnemonic – SDS = Small (both start with S)
▪ SDS – SDS is a chemical that denatures proteins by disrupting any non-covalent
associations they may have.
• This makes it so that the differential charge of the different proteins
isn’t a factor when they are separating out onto the gel, and thus they
are only being separated out by size.
▪ PAGE – stands for polyacrylamide gel electrophoresis… polyacrylamide is the
substance that the gel is made out of.

o ELECTROPHORESIS– encourages sample to move by passing an electrical field through the gel.
o Electrolytic cell with a cathode & anode (opposite rules to what you might expect):
▪ At the cathode, reduction takes place, so there will be a (–) charge
• Mnemonic – RED CAT – reduction always occurs at the cathode
▪ At the anode, oxidation takes place, so there will be a (+) charge
• Mnemonic – AN OX – oxidation always occurs at the anode
• NOTE: actual cathode/anode charge is opposite in Galvanic cells
o Requires a battery to power & connect the cathode and anode (since it is electrolytic)
o Requires a buffer (a conductor of electricity so that charge can flow across)

Process:
o Samples are loaded into individual wells alongside a dye (for visualization as its running).
o Electrical field is turned on.
o Since DNA has a negative charged backbone (due to the negatively charged phosphate
groups), it will travel away from the cathode end (–) and towards the anode end (+).
o One well contains a DNA ladder, which provides a reference to known fragment sizes.

Simple rules for gel electrophoresis

o Smallest fragments -> Furthest travelled
 Resolution (separation) of enantiomers

Chiral column chromatography

o Allows for resolution of a racemic mixture of enantiomers
o Stationary phase is chiral, meaning that it will either bind to either the R or S conformation
but not both.
o Think of it like:
▪ A right hand shaking a right hand – normal, works just fine.
▪ A right hand shaking a left hand – don’t fit together right.

Gas chromatography
o Same idea as above.
o Stationary phase is chiral, meaning that it will either bind to either the R or S conformation
but not both.

Key concept and take-home message – racemic mixtures of enantiomers can be separated by
chromatography by using a chiral stationary phase, meaning that it that can bind/interact with one of
the two enantiomers
Nucleic acids, lipids and carbohydrates

Nucleic Acid structure

DNA -> DNA wrapped around histones -> Chromatin -> Chromosomes

DNA has 3 components:

1) Pentose sugar: deoxyribose (ribose for RNA)
2) Nitrogenous bases (adenine, thymine, cytosine, guanine)
3) Phosphate group
Nitrogenous bases:
PURINES – Adenine, Guanine
• 2 rings
• Mnemonic: 2 bases in category = 2 rings
• Mnemonic: PURE As Gold

PYRIMIDINES – Cytosine, (Uracil), Thymine,

• 1 ring
• Mnemonic: CUT

The nitrogenous bases always pair up via hydrogen bonding

C≡G 3 hydrogen bonds, stronger, harder to denature
A=T 2 hydrogen bonds, weaker, easier to denature
Antiparallel structure of DNA strands

Backbone of DNA is a chain of alternating negatively charged phosphates and pentose sugars, linked
together by phosphodiester bonds, forming a phosphate-deoxyribose backbone

The commentary nitrogenous bases link the two backbones of DNA together in an antiparallel
structure
• See how the oxygen on the pentose sugars are pointing in opposite directions on opposite
strands.
• 5’ and 3’ refer to carbons on the pentose sugar.
o The 5’ end has a phosphate group ready to bind the 3’ end of another pentose sugar.
o The 3’ has a free OH ready to bind the phosphate on the 5’ end of another pentose
sugar.

Although the bases have nitrogen (making them a base), the phosphate groups are acids when
protonated, and thus DNA is said to be an acid (deoxyribonucleic acid)
• Tend to draw phosphate groups deprotonated, since they’re so acidic that they dissociate
from the protons easily.
Lipids - structure in cell membranes

Note on functional groups before content starts:

Ester group functional group:

Phosphodiester functional group:

CONTENT:

2 main categories of lipids:

1 | Hydrolysable – can be broken down into smaller units
o All hydrolysable lipids can be broken down by hydrolyzing the ester group via an ester-
hydrolysis reaction.

o Triacylglycerol aka Triglyceride (TAG) – energy storage

o Phospholipid (PL) – structural function
o Sphingolipid – structural function
o Waxes – structural function

2 | Non-hydrolysable – cannot be further broken into smaller units

o Main function is signaling and acting as co-factors.

o Prostaglandins
o Steroids
o Vitamins
 HYDROLYZABLE LIPIDS
Phospholipids
• Hydrolysable
• Contain a phosphorous atom in the form of a phosphodiester bond:
o ‘ester’ because the central atom (phosphorous) is double bonded to an oxygen and
single bonded to an OR group
o ‘di’ because it happens twice (i.e. P is single bonded to two different OR groups)

• Now if we take a TAG and replace one of the FA chains with our phosphodiester unit, we will
now have a PL, which now has both a non-polar and a polar region:

------------>
TAG PL

• Due to this property of having two regions, a non-polar and a polar region, PLs can line up and
form cell membranes as a PL bilayer, where non-polar ‘tails’ face each other and the polar
‘heads’ face outwards.
 continued
Sphingolipids
• Hydrolysable
• Again, utilizes the phosphodiester unit.
• The starting point in this case is sphingosine (rather than TAG)
o Sphingosine is an amino alcohol, with lipid characteristics and a 15-carbon tail
• Sphingolipids have a structural function in the myelin surrounding nerve cells.

Waxes
• Waxes consist of an ester formed from two molecules:
o Long carbon chain alcohol (ROH)
o Long carbon chain FA (R-COOH)

• Unique in a sense that it has two very long carbon chains (non-polar) on either side of the
ester.
o These 2 large non-polar sections make waxes very hydrophobic
o Explains why wax is so water resistant
Lipids as cofactors and signaling molecules

NON-HYDROLYZABLE LIPIDS

Non-hydrolysable lipids cannot be broken down into smaller units.

Their main functions are signaling molecules (ex. prostaglandins signaling inflammation) and acting
as cofactors (ex. Vitamins E as an antioxidant)

Prostaglandins (PG):
• Lipids that function as signaling molecules
• PGs belong to a group called the eicosanoids:
o eico- greek for 20
o All in this group have 20 carbons
o Eicosanoids are known for being local mediators (i.e. signals an effect in their
immediate environment)

• Roles:
o Signal inflammation
o Signal to lower BP
o Signal to decrease gastric secretions
o Signal to inhibit platelet aggregation

Steroids
• Lipids that function as signaling molecules
• Tetracycline (meaning they have 4 cyclic rings)
• Examples:
o Cholesterol
o Testosterone (top)
o Progesterone (bottom)

Fat-soluble vitamins:
• Lipids that function as cofactors – factors that the body cannot synthesize on their own (i.e.
must be acquired in our diet), but are required to help specific enzymes in our body perform
their specific function
• Examples of fat-soluble vitamins:
o A: (aka retinol) – light sensitivity and mucous membranes
o D: – regulates phosphorus and calcium metabolism
o E: – antioxidant protecting neurological function
o K: – regulates synthesis of prothrombin (helps in blood clotting)
Saponification - Base promoted ester hydrolysis

TAGs are hydrolysable lipids meaning that they can be broken down into smaller pieces via an
ester hydrolysis reaction:

(See where the slashes are on the diagram)

Saponification – the ester hydrolysis reaction occurring between any fat (e.g. TAG) and sodium
hydroxide (NaOH).

Ester hydrolysis reaction can occur in both acid and base conditions. We will focus on the latter.

Base-promoted ester hydrolysis

1) –OH group of the base (in blue) nucleophillically attacks the C on the ester, forcing one of the
bonds (2 of the electrons) from C=O to move onto the O (oxygen readily accepts these electrons,
since it is relatively electronegative).
2) Tetrahedral intermediate. The electrons from the top O next reform the C=O bond, which forces
the electrons from the C-OR bond to go to the O of the –OR group, pushing it out. This makes the
negatively charged –OR group the leaving group and a strong base.

3) This has led to the formation of a carboxylic acid. Now there is an acid-base proton transfer with
the –OR group (strong base) that just left (acid – electron acceptor) (base – electron donor)

End product is carboxylate anion + alcohol (R-OH)

See how the C-OR bond in the original ester has been broken.

Applications of this reaction:

1) In the body, this saponification via base-promoted ester hydrolysis is the starting point of all
fat metabolism reactions, and is facilitated by lipases.
2) Creation of soaps
• If you use NaOH as the base for base-promoted ester hydrolysis, then step one
leaves an Na+ cation just ‘floating’ around, which is unused until the final step
where it will associate with the negative charge of the carboxylate anion, forming
an ionic salt.
• If it so happens that the carboxylate anion formed from the ester hydrolysis of a
TAG, then the R group (on the left) is actually a FA tail.
• Thus, the ionic salt will have a really polar head and a long non-polar section
• These properties of this ionic salt make it a soap that is capable dissolving both
polar molecules (with its polar head) such as water, and non-polar molecules (with
its non-polar tail) such as grease, oil.
Fischer projections

A way to visualizing molecules in 3D.

Note: This information uses absolute configuration notations (S and R)

However, traditionally Fischer Projections will use Fischer Projection notations (L and D), which will
be shown in the next lecture.

LACTIC ACID example

Lactic acid has only one chiral center (starred)

After assigning priorities to the atoms attached to the chiral carbon center (based on atomic
number), we can determine that lactic acid has an R configuration (CW rotation)

First step is to look at the figure from the top (represented by an eye) and draw a line (represented
by the dotted lines) across the chirality center that represents the ‘flat piece of paper’
This configuration can now be redrawn without the dashes and wedges, instead using simple straight
lines, to form the Fischer projection.

Fischer projection Think: Solid bowtie, striped tie

By Fischer projection convention, lines going up and down on a page are going away from you in
space (‘into the paper’), and lines going left or right are coming towards you in space (‘out of the
paper’)
––

If we were to look at the enantiomer of this Fischer projection, we draw the mirror image and we see
that we get an S configuration.
 4 CARBON CARBOHYDRATE example

Has two carbon chiral centers, and therefore 2n = 22 = 4 possible stereoisomers of this molecule

Now starting with the saw-horse projection of one of the possible stereoisomers.

1) Add the eye and the line for the piece of paper across the chiral centers (blue dots below).
2) Redraw from the perspective you see.
3) Redraw once more but with dashes and wedges becoming straight lines to get the Fischer
projection

The four possible stereoisomers would be drawn like this:

Non-superimposable, mirror images (enantiomers):

• A&B
C&D
Non-superimposable, non-mirror of each other images (diastereomers)
• A&C
• A&D
• B&C
• B&D

How can you determine absolute configuration (R or S) from a Fischer projection?

Go back a step and redraw it with dashes and wedges, and two of the atom for double bonds

Assign priority around the chiral center at carbon 2

Use the trick whereby if the hydrogen (priority 4) is coming out at you, and it looks like ‘S’, then flip
the configuration to get your true configuration = R.

You’d then have to assign R or S to the chiral center at carbon 3 too. If you did this, you’d find that it
happens also to be R, and thus this is a 2R, 3R stereoisomer. This would different between the 4
different stereoisomers.
Additional information on Fischer projections from SparkNotes:

–––––––––––––––––––––––––––––––––––––––––––––
Side note on functional groups:

Aldehyde

Ketone
Carbohydrates – naming and classification

Carbohydrate – a chemical compound made of carbon atoms that are fully hydrated

Chemical formula of Cn(H2O)n

• 1:1 ratio of C:H2O
• 1:2:1 ratio of C:H:O

Saccharide = Sugar (Greek) = Carbohydrate = CHO

• Monosaccharide: 1 saccharide
o Ex. Glucose – 6 carbon monosaccharide, primary energy source in our body.
• Polysaccharides: Several carbohydrates linked together
o Ex. Cellulose – makes up the structural backbone of cell walls in plants
o Ex. Ribose – 5 carbon polysaccharide, key component of RNA

Naming:
• Suffix: Suffix for sugars –ose

• Prefix: Number of carbons in the chain –Tri– 3

–Tetr– 4
–Penta– 5
–Hex– 6

• Pre-prefix: Functional group –Aldo– Aldehyde funct. group

–Keto– Ketone funct. Group

• Pre-pre-prefix: Fischer stereochemistry L–

D–

Examples – glyceraldehyde has 3 carbons and an aldehyde functional group -> aldotriose
– glucose has 6 carbons and an aldehyde functional group -> aldohexose
– fructose has 6 carbons and a ketone functional group -> ketohexose

Stereochemistry – Fischer Projection notations (L and D)

L and D are ways to refer to stereochemistry of a molecule, but they don’t consider the optical
activity of the molecule (like the S and R notation does)
• The LD and SR systems don’t match up, so don’t interchange them.
• A molecule can be D (right at last chiral carbon) and still be overall S (CCW counting)

Assigning L and D stereochemistry:

• First, locate the longest carbon chain and number the carbons (whereby numbering should
give the lowest numbers possible to the groups appending from the parent chain).
 • Next, look at the penultimate carbon (the carbon with is one carbon before the last carbon in
the chain) (aka the ‘last’ chiral carbon in the chain, or the highest numbered chiral carbon)
and determine whether the hydroxy group is to the left (L) or right (D) of the chain.
o D = Dexter (latin) = Right
o Mnemonic: Dexter’s thinks his killing is right because he only kills bad people

Example: Glyceraldehyde

L-aldotriose ex. D-aldotriose ex.

Examples: Glucose and Fructose

D-aldohexose ex. D-ketohexose ex.

Carbohydrates - Epimers, common names

Humans have the enzymes to break down and digest the “D” sugars.

The configuration of the -OH groups distinguishes between molecules with the same functional
group, the same number of carbons and the same configuration on their final chiral carbon.
• Ex. D-aldohexoses
o All have aldehyde functional groups
o All have six carbons
o All have the -OH of the last chiral center to the right (since they’re D configuration).
o -> They differ in terms of which side the rest of their -OH groups are on
▪ Thus, all the D-aldohexoses must diastereomers of each other (since they’re
different at some but not all chiral carbons, and are therefore non-
superimposable, non-mirror images)
▪ It is of course true then that all the L-aldohexoses are diastereomers of each
other too, or L-ketopentoses, etc…

Thus, to maintain the same name between the D- and L-configuration of the same molecule, the D-
and L- configurations of the same molecule (e.g. D-glucose and L-glucose) must be differ from each
other (i.e. be opposites) at every chiral carbon, or else you’ll be getting something other than
glucose.

Thus, D-glucose and L-glucose must be enantiomers (since they different at every chiral carbon, and
are therefore non-superimposable, mirror images)
This is true, of course, for the D- and L-configuration of any of the D-aldohexoses, and for D-
ketopentoses, and for… etc.

The last term to know is epimers – diastereomers that differ only at a just one chiral center.
• Example: Glucose and Galactose – differ only at carbon 4.

––––––––

Determine the number of variants for a particular group:

Example: Aldohexoses
• 6 carbon molecules in total, but only 4 chiral centers
• Thus, there are 24 = 16 possible stereoisomers.
• Half will have the -OH on the final chiral center to the left, the other half to the right:
• 8 L-aldohexoses, 8 D-aldohexoses

Example: Ketohexoses
• 6 carbon molecules in total, but only 3 chiral centers (see structure example)
• Thus, there are 23 = 8 possible stereoisomers.
• 4 L-ketopentoses, 4 D-ketopentoses
5 most commonly seen monosaccharides (and mnemonics to remember them):

1) D-ribose (aldopentose)
• Ribose is “all right” – all the OH on the right side

2) D-glucose (aldohexose)
• Glucose flips people off because it knows it’s the best source of carbon and it is cocky about it
o Put right hand (D) as you would if you were flipping someone off
o Thumb is to orient yourself with the aldehyde group at the top
o Curled fingers point in the direction of OH groups

3) D-mannose (aldohexose)
• Mannose is the man around town, and will challenge you to a duel with his hand-gun.
o Make right hand into a gun with a two-finger barrel.

4) D-galactose (aldohexose)
• Just remember that it’s the c4 epimer of glucose

5) D-fructose: (ketohexose)
• Just remember that it’s the ‘ketose version of glucose’
• Note that the ketone group is not where the aldehyde group is, it’s ‘one down’, since of the R
group can’t be just H (or else you’ve just got an aldehyde again). The R group = CH 2OH
Carbohydrates – Cyclic structures and anomers

Ring closing process occurs due to the addition of some amount of acid and base.

The process involves a reaction between the carbonyl carbon (a carbon that is involved in a C=O
bond, found in aldehydes, ketones, and other functional groups) and one of the hydroxyl groups
(alcohol group).

OH > 1 (excess of alcohol) Product is an acetal or a ketal

OH = 1 (one nucleophilic attack by attack) Product is a hemiacetal or a hemiketal
o Hemiacetals and hemiketals are compounds that are derived from aldehydes and ketones
respectively.
o These compounds are formed by formal addition of an alcohol to the carbonyl group.

Process of hemiacetal or hemiketal formation:

The partial negative character (δ–) of oxygen (O) allows it to act as a nucleophile to then attack the
partially positively charged (δ+) carbonyl carbon (C). Recall that this polarization occurs due to the EN
of O, which causes O to ‘hog’ the electrons just a little more.

Two electrons from the C=O double bond get transferred to the oxygen. From there, these electrons
will then attack another proton forming a new hydroxyl (OH) group.

Why does a ring form in the first place? Why is it that specific oxygen (O) that acts as the
nucleophile?
• A ring confers more stability than the straight carbon chain. This particular oxygen is used
because it forms the most stable of the possible rings. Chemical processes favor stability. In
the case of glucose, this comes as a 6-membered ring.

Pyranose – Sugar in the form of a 6 membered-ring

Furanose – Sugar in the form of a 5 membered-ring
• Mnemonic – Five Fura, both start with F

Haworth diagram / projection – used to represent cyclic structures of monosaccharides in 3D

• By convention:
o Nucleophilic O gets the ‘top right’ position.
o Carbonyl C (now bound to the nucleophilic O) gets the name ‘anomeric carbon’.

• The Haworth projection tells us which substitutes are above or below the ring.
o “Down-right up-left-ing”, a play on the phrase “downright uplifting”
▪ Substituents on the right of the Fischer diagram point down
▪ Substituents on the left of the Fischer diagram point up
o The final carbon (C6) of a Fischer diagram isn’t to the left or right, so it follows a
different rule:
▪ L-sugars: Final carbon points down
▪ D-sugars: Final carbon points up
Chair conformations
• Provides information about the actual shape of the ring
• The substituents follow the same as the Haworth diagram in terms of what is pointing up or
down.
o However, we didn’t assign an ‘up or down’ for the -OH group on the anomeric carbon
(C1) in the Haworth diagram, so we need to do that now.
o This will depend on whether the nucleophilic attack produced an R or S configuration
around the anomeric carbon, and results in one of the two following possibilities:
▪ β-anomer: OH is cis (same) to C6 (i.e. up for D-sugars)
▪ α-anomer: OH is trans (opposite) to C6 (i.e. down for D-sugars; α looks like a
fish in the sea)

• Each carbon that has something ‘sticking off of it’ has one axial (completely straight) and one
equatorial (slanted towards whichever side it is on), and of these one is up while the other is
down.
o Up-equatorial + Down-axial ––– Down-equatorial + Up-axial (sequentially around ring)

o So long as you remember one of the starting points (e.g. bottom left carbon has an
upwards equatorial – slanted), then you can draw in all the rest by alternating.

o The larger substituents prefer to be equatorial position (slanted) (which explains why
we see the OH groups generally in the equatorial positions)

Some amount of acid or base is what causes this ring to close in the first place
• In water, the ring can open or close spontaneously.
• Mutarotation – when open, the C1–C2 bond can actually rotate, and upon closing again can
be in either the α or β form.
o This outcome is that both the α or β product are present in equilibrium.
o The proportions of each are different for different sugars
 o Generally, the β-form is favored, because the larger substituents prefer to be in the
equatorial position rather than the axial position.
o Example: Glucose at equilibrium in water is 36% α form and 64% β form

Carbohydrate – Glycoside formation hydrolysis

How do we progress from a hemiacetal ––> acetal?

1 OH group, 1 OR group around anomeric carbon Two OR groups around anomeric carbon

Note on naming: OH = hydroxyl group OR = alkoxy group

General process:
o Dehydration of the hemiacetal (H joins the OH and is lost as water) makes room for the
second -OR group.

Glycoside – a molecule in which a sugar is bound to another functional group via a glycosidic bond.
o Example: Dehydration of glucose (hemiacetal) followed by additional of a functional group
forms a glucoside (acetal) (a type of glycoside).
 Mechanism of glycosidic FORMATION (via DEHYRATION)

o β-D-glucose (hemiacetal) in the presence of a strong acid (HCl) will undergo protonation of
the OH on the anomeric carbon
o What really happens but is not shown on the diagram:
o HCl + H2O –> Cl– + H3O+
▪ Now it is H3O+ that actually protonates the OH on the anomeric carbon.
o The protonated OH group (H2O – water) is a good leaving group, leading to dehydration (loss
of the water molecule)
o Since water leaving produces a carbocation (a carbon with a positive charge), the carbon is
resonance stabilized by the oxygen in the top right position.

o The carbocation is in a “planar” nature.

o This planar nature allows the next alkoxy group (which in this case is on a nucleophilic
alcohol, CH3OH) to either attack from above or below.
o After the nucleophilic attack, the oxygen that just joined now a positive charge.
o The Cl– anion that was created in earlier steps ‘takes back’ the extra proton, allowing the
previously shared electrons to go back to the oxygen as a lone pair, removing the positive
charge from the newly joined oxygen.
o Depending on if the nucleophilic attack occurred from above or below, the resulting glycoside
can either be an α- or β-glycoside (same cis/trans rules compared to C6 as before).
 Mechanism of glycosidic HYDROLYSIS (via HYRATION)

The previous reaction was a dehydration reaction that allowed the formation of glycosides.

The following reaction is the reverse – a hydration reaction that breaks down these poly-unit
molecules (hydrolysis – lysis by hydration)

• The alkoxy group ‘pulls’ a proton (hydrogen) off of a hydronium ion (H3O+), producing water
as a byproduct.
• This particular alkoxy group (CH3OH) now bears a positive charge, and makes a good leaving
group, and is lost.
• We again get an intermediate structure that is resonance stabilized, planar carbocation.
• A water molecule (produced in the previous step) can now come in and nucleophillically
attack either above or below the carbocation to remove the positive charge from the carbon.
• The positive charge (extra electrons) now reside on the oxygen of the water that just joined.
• Another water molecule can then remove the additional proton on the oxygen to stabilize this
as a neutrally charged hydroxyl group (and also reforming the H3O+)
• Since there were two directions from which the water could nucleophilically attack, the result
is 2 possible end products (depending on location of nucleophilic attack):
o α-D-glucose or β-D-glucose (like we started with two pages ago)
Disaccharides and polysaccharides

Multiple units of monosaccharides (hemiacetals) can link together via glycosidic linkages to form
disaccharides or polysaccharides
• Disaccharides: 2 monosaccharides linked by glycosidic linkages
• Polysaccharides: 3 or more monosaccharides linked by glycosidic linkages

––– DISACCHARIDES –––

Disaccharides – 2 monosaccharides linked by a glycosidic linkage

Glycosidic link:
• Disaccharides typically have 1,4’ glycosidic linkages, meaning that they are formed between
C1 (the anomeric carbon) of the first sugar, and C4 of the second sugar.
• Based on the orientation of the OR group (i.e. the second sugar) with respect to the C6 of the
first sugar, we can further label a disaccharide as αlpha (trans with respect to C6 of first
sugar) or βeta (cis with respect to C6 of first sugar) linkage.

Common disaccharides:
• Lactose:
o (Pyranose) Galactose – β-1,4’ – Glucose (Pyranose)
o The ring to the left is an acetal and the ring to the right is a hemiacetal.
▪ A reducing sugar is any sugar that is capable of acting as a reducing agent
because it has a free aldehyde group or a free ketone group. Lactose is a
reducing sugar (since it can glycosidic linkages with other carbohydrates and
thus elongate the chain).

• Maltose:
o (Pyranose) Glucose – α-1,4’ – Glucose (Pyranose)
o Again, the ring to the left is an acetal and the ring to the right is a hemiacetal.
▪ Thus, maltose is also a reducing sugar.

• Sucrose:
o The most common disaccharide
o (Pyranose) Glucose – α-1,2’ – Fructose (Furanose)
o Sugars are both linked together by their anomeric carbons.
o Thus, we have an acetal group (a carbon linked to two OR groups) on each side of the
linkage.
o Since both rings are acetals, and you can’t further reduce an acetal, no further
glycosidic linkages can be made, and therefore sucrose is a non-reducing sugar.
 ––– POLYSACCHARIDES –––

A continuous chain of reducing sugars where an acetal group and hemiacetal group is added each
time, such that the chain can keep extending.

Cellulose:
• Made of repeating glucose units joined together by β-1,4’ glycosidic linkages.
• Found in the cells walls of all plants (support and structure)
• Humans do not have enzyme to break down these linkages.

Starch:
• Made of repeating glucose units, but this time joined together by α-1,4’ glycosidic linkages.
• Humans do have the enzyme to breakdown these linkages, and thus we can use starch as a
source for glucose in our diet (‘starchy foods’)

Glycogen:
• Very similar to starch (glucose strung together), but with an occasional branch off of the C6
carbon (i.e. α-1,6’ linkages).
• Thus, glycogen contains both α-1,4’ and α-1,6’ linkages
Amino acids, peptides and proteins

Central dogma of molecular biology

As proposed by Watson & Crick:

DNA → RNA → Protein

DNA & RNA: made of nucleic acids

protein: made of amino acids

Information at the most basic level is stored as DNA which can then be re-stored as DNA (copies itself
in a process called replication)

DNA can then be copied into RNA in a process called transcription.

With the information contained in RNA we synthesize proteins in a process called translation.

DNA, RNA and proteins are linear polymers, meaning that each individual monomer is only attached
to, at most, two other units. The specific sequence of each monomer thus encodes information.
The transfer of this sequence is then preserved from DNA to RNA to protein. Each polymer sequence
is used as a template for the synthesis of the next polymer
Central dogma – revisited

Some new theories that contradict the findings as proposed by Watson and Crick.

Reverse Transcription: Info flows backwards from RNA to DNA

using the enzyme reverse transcriptase (RT) that generates cDNA
(complementary DNA) from an RNA template. RT is needed for
the replication of retroviruses (ex: HIV), using the host’s genome
to replicate its own DNA.

RNA Viruses: Viruses that have their genetic material stored as RNA that
can have their genome directly used by the host cell replication
machinery as if it were mRNA (messenger RNA) and then translated
directly into protein. Alternatively, they can have their RNA serve as a
template for another RNA strand which is then used for protein
translation. (ex: coronavirus- SARS, influenza virus- flu)

ncRNA (noncoding RNA): ncRNA is a functional RNA that skips the last step
of being translated into a protein. It can directly perform functions within
the cell as an RNA molecule.
(ex: tRNA and rRNA)

Epigenetics: the study of heritable changes in gene activity that are not
caused by changes in the DNA sequence. This is not like simple genetics
where change in phenotype = change in genotype.
It’s the mechanism where the same DNA sequence can be modified
resulting in a different phenotype without any changes in the underlying
DNA sequence. (ex: DNA methylation, histone modification). This basically
explains why you have the same DNA in all cells of your body but those
cells don’t necessarily look or behave the exact same way. It allows the
transcriptions of only certain genes within the genome.
Alpha amino acid synthesis

2 methods to synthesize amino acids

1) Gabriel synthesis:

a) N-phthalimidomalonic ester (“Thad”) is alkylated (alkyl group R-X) using a base. Alkyl
group has now be substituted onto the carbon.
b) Acid hydrolysis (using H3O+) leads the phthalimide group being hydrolyzed along with the
2 esters
c) Using heat, the molecule is decarboxylated (on the upper group) and we get our alpha-
amino acid.

2) Strecker synthesis:
Considered as an “elegant” way to synthesize AAs, since it is more simple and efficient
3 essential components:
1) NH3: precursor for amino group
2) KCN (potassium cyanide): precursor for the carboxylic acid group
3) aldehyde or ketone: carbon scaffold on which amino and carboxylic acid groups will be
bound
The mechanism is seen below (all steps occur in the presence of acid)
Chemistry of amino acids and protein structure (article)

Proteins are large, complex molecules that

are critical for the normal functioning of the
human body. They are essential for the
structure, function, and regulation of the
body’s tissues and organs. Proteins are
made up of hundreds of smaller units called
amino acids that are attached to one
another by peptide bonds, forming a long
chain. You can think of a protein as a string
of beads where each bead is an amino acid.

Amino acid structure and its classification

An amino acid contains both a carboxylic group (COOH) and an amino group (NH2). Amino acids that
have an amino group bonded directly to the alpha-carbon are referred to as alpha amino acids. The
simplest representation of an alpha amino acid is shown below.

Every alpha amino acid has a carbon atom, called an alpha carbon,
Cα; bonded to a carboxylic acid, –COOH, group; an amino, –NH2,
group; a hydrogen atom; and an R group that is unique for every
amino acid. If you notice in the structure above, Cα is a chiral center,
that is to say, this carbon atom is attached to four different groups.
Chirality refers to a molecule that has optical activity, so amino acids
are optically active molecules. The only exception is glycine, the
simplest amino acid, in which R = H.

Commonly, amino acids are represented as follows:

 L and D amino acids

As shown above, L and D amino acids are mirror images of each other and are non-superimposable
on each other, just like our left and right hands. By non-superimposable, we mean that when the
mirror image of the object is placed over the original object, they do not have a perfect overlap. Pairs
of amino acids like these are called enantiomers.
• No L or D form for glycine, since it is non-chiral.

All chiral amino acids in our protein have the L-configuration, and our body synthesizes most of its
own L-amino acids

• Mnemonic: L=Link=Linked AAs to make a protein

• Note: our body digests D-sugars but not L-sugars – think of it like L-being our own, we don’t
want to digest that down, but D being foreign, things that we take in and want to break down.

Proteins are catalysts for most of the biochemical reactions that take place in our body. Along with
DNA and RNA, proteins constitute the genetic machinery of living organisms. Proteins are often
called the building blocks of life.

Isoelectric point (pI) of amino acids

Isoelectric point – the point along the pH scale where the amino acid has a net neutral (zero) charge.

Ex: glycine. Look at the equilibrium below; as we add hydroxide ions—in other words, alkalify/raise
the pH—different charged forms of glycine exist.
Form A has a net charge of +1
Form B has a net charge of 0. Form C has a net charge of -1.

Zwitterion – a neutral molecule with both positive and negative charges present (ex. ‘B’ above)
The titration curve of glycine is shown below.
• pH=2.34 (pKa1) – forms A and B will be in equilibrium concentration (equal concentrations)
• pH=9.6 (pka2) – forms B and C will be in equilibrium concentration (equal concentrations)

The isoelectric point (pI) is calculated using the following formula (for neutral side chains):

ex. glycine:

Every amino acid has a different pI, which largely depends on the nature of the side chain present.

pKa = point at which the protonation state changes.

pKa1 = carboxyl group
pKa2 = ammonium ion group
pKa3 = only for acidic or basic side chains
Example – see how at every pKa, the group that is specific to that pKa changes in its state of
protonation.
 Classification of different amino acids

There are 20 common amino acids. Based on the nature of the R group, they are classified as follows:

• Hydrophobic – non-polar side chains, such as alkyl groups or aromatic groups.

o Note – includes glycine (though since glycine lacks an R group, it’s hard to classify)
• Hydrophilic (neutral) – polar side chains, such as hydroxyl, -OH and sulfhydryl, -SH, groups.
• Hydrophilic (acidic) – side chains contain carboxylic acid groups, COOH.
• Hydrophilic (basic) – side chains contain amine groups, -NH2,
o Note – includes histidine
 How are amino acids joined together?

Amino acids are joined together through peptide bonds.

Peptide bonds are covalent bonds formed by the nucleophilic addition-elimination reaction
between the carboxylic group of one amino acid and the amino group of another amino acid

This reaction releases a water molecule as the by product. A peptide bond is essentially an amide
bond.

Mechanism of peptide bond formation

The simplest way to represent a peptide bond formation is as follows. Let’s consider two amino acids
with side chains, R1 and R2 respectively.

Step 1: The nucleophilic amino group of the AA2 attacks the electrophilic carbonyl group of the AA1,
resulting into a molecule with a negatively charged O and a positively charged N
Step 2: The carbonyl bond (C=O) reforms by the elimination of a hydroxide ion (OH–), which
neutralizes the positive charge of the O.
Step 3: The hydroxide ion takes a proton from the positively charged N, leading to elimination of
water and neutralization of the positive charge on N.

This results in the formation of a new bond—a peptide bond between the two amino acids.

Please note that this is a very simplistic representation of the mechanism of a peptide bond
formation. The mechanism gets complicated in the context of peptide-protein synthesis in biological
systems where catalysts, cofactors, and enzymes are involved.
 The double-bond character of the peptide bond

If you were asked to draw a peptide bond, you might draw a single bond between the nitrogen and
the carbonyl carbon atoms. But in reality, this single bond is not a conventional single bond; in fact, it
has a double-bond character.

This double-bond character comes from the various resonance structures of a polypeptide.

Resonance structures are different representations of the same molecule; the arrangement of the
atoms remains the same, but the electrons are distributed differently amongst the atoms. Resonance
structures exist when there is a possibility of movement of electrons between neighboring functional
groups, as is the case of polypeptides.

Electrons can move across the amide bond, C-N and onto the carbonyl bond, C=O, generating the
two structures A and B respectively.

Structure C is the overall hybrid representation of the two resonance structures A and B, where the
entire peptide bond, O=C-N, is shown to have a partial-double-bond character, represented by a solid
line with a dotted line running parallel to it.

So, as a result of resonance, the bond between the carbonyl carbon and nitrogen acquires a partial-
double-bond character, and, just like any double bond, rotation around this peptide bond is now
restricted.

Also, as with all double bonds, the atoms of the peptide bond have planar geometries. This planar
geometry causes the peptide bond to be either in the cis or the trans configuration.
 • In the cis configuration, the two alpha carbon atoms fall on the same side of the peptide
bond.
• In the trans configuration, these groups are on opposite sides of the peptide bond.

Summary:
 Different levels of protein structure

The four levels of protein structure are: primary structure, secondary structure, tertiary structure,
and quaternary structure.

Analogy: Alphabet -> Words -> Sentences -> Paragraphs

1° -> 2° -> 3° -> 4°

Primary structure
• Simply refers to the linear sequence of AAs joined to each other through peptide bonds. The
sequence of amino acids determines the basic structure of the protein.
Secondary structure

Unlike the rigid peptide bond, the bond linking the

amino group to the alpha carbon atom (of the same
AA) and the bond linking the alpha carbon atom to the
carbonyl carbon (of the same AA) are single bonds.
These two bonds are free to rotate about the amide
bonds, allowing the amino acids in the polypeptide
chain to take on a variety of orientations.

The enhanced freedom of rotation with regards to these single bonds allows proteins to fold into a
variety of shapes. These folded structures are referred to as secondary protein structures and are
essentially of two types
• α-helix
• β-pleated sheets

These folded secondary structures are stabilized by the formation of hydrogen bonds between the
amino acids.

α-helix:
• AAs get oriented in such a manner that the carbonyl group, C=O, of the (n)th AA can form a
hydrogen bond with the amino group, N-H, of the (n+4)th AA in the same polypeptide chain.
• Hydrogen bonding is occurring between every C=O and N-H group of all AAs with this spacing.
o (AA1) C=0 - - - H-N (AA5)
o (AA2) C=0 - - - H-N (AA6)
o (AA3) C=0 - - - H-N (AA7)

• This results in a strong hydrogen bond that has an optimum H-to-O distance of 2.8 Å.
• The hydrogen bonds between the AAs stabilize the α-helix structure.
β-pleated sheet:
• Hydrogen bonding occurs between neighboring polypeptide chains rather than within the
same polypeptide
• β-pleated sheets exist in two forms:
o Antiparallel – neighboring hydrogen-bonded polypeptide chains running in opposite
directions (i.e., one polypeptide chain starts from the terminal carboxylic group and
ends at the terminal amino group, while the other polypeptide chain starts from the
terminal amino group and ends at the terminal carboxylic group)
▪ 1 AA forms 2 hydrogen bonds, both to the same 1 other AA.
o Parallel – hydrogen-bonded chains extending in the same direction.
▪ 1 AA forms 2 hydrogen bonds, each to a different AA.
Tertiary structure
• When several secondary structures come together, tertiary structures are formed.
• In tertiary structures, in addition to hydrogen bonding, AA side chains of the various
secondary structures start interacting with each other in a number of ways.
o These interactions include hydrophobic interactions, ionic interactions, disulfide
bonds, and VdW forces

• Hydrophobic packing – a protein folded within watery polar environment will have an
exterior dominated by polar interactions and an interior dominated by nonpolar interactions

Quaternary structure:
• When several tertiary structures come together, a quaternary protein structure is formed.
• The same forces of interactions operate in a quaternary structure as operate in a tertiary
structure.
• ex. Hemoglobin is a functional quaternary protein formed by the coming together of four
tertiary structures, called globin proteins.
• # of polypeptides: 1=monomer
2=dimer
3=trimer
4=tetramer

Amyloid: clump of misfolded protein

Summary

Level of protein structure Description Interactions that stabilize the

structure
Primary (1°) Linear polypeptide with its AA Covalent bond
sequence (i.e. the peptide bond)
Secondary (2°) Folded version of 1°, stabilized Hydrogen bonds
by hydrogen bonding
Tertiary (3°) Several 2° structures come Ionic bonds
together and are held together Disulfide bonds
by various types of interactions Hydrophobic interactions
Quaternary (4°) Several 3° structures come VdW forces
together to form a multi- Hydrogen bonds
subunit complex, held together
by the same interactions acting
in 3° structure
Peptide bonds: Formation and cleavage

Amino acids are linked together by peptide bonds. Multiple peptides make polypeptide chains.
Folded polypeptides make proteins.

How are peptide bonds formed? (below)

There is a nucleophilic addition-elimination reaction between two amino acids.
1) The electrons from the amino group of the 2 nd amino acid forms a bond with the carbonyl
carbon from the 1st amino acid. Water is released.
2) We now have our newly formed dipeptide with the peptide bond (drawn in yellow). This
dipeptide is resonance stabilized as seen in the structure to its right where the electrons from
the nitrogen causes a formation of a double bond

More amino acids can be added to this chain and we can notice a pattern forming in the backbone as
seen in the lowest structure below (this pattern is repeated as more amino acids are added):
Nitrogen—alpha-carbon—carbonyl carbon—REPEAT

Left side is always N terminal and right side is C terminal

How do we breakdown this bond? (figure below)

Using hydrolysis (‘lysis using water’) we can go back and get the amino acids (makes sense, since
water is lost in the formation, addition of water would reverse the process).

The hydrolysis of a peptide bond is accomplished by:

1) Strong acids: acid hydrolysis combined with heat is a nonspecific way of
cleaving peptide bonds.
2) Proteolytic enzymes: Specific cleaving done by a protease.
 • You can choose which polypeptide bonds to cleave, for ex: trypsin only cleaves on the
carboxyl side of basic amino acids like arginine and lysine.
• In the example to the bottom right, trypsin would cleave that polypeptide into 3
fragments (cleavage sites are the red arrows)

Special cases: histidine, proline, glycine, cysteine

Special due to their side chains, which sets them apart from the other AAs.

Histidine: pKa of histidine’s side chain (pKa3)

= 6, which is close to physiological pH (7.4).

Thus, the histidine will exists in both

protonated and deprotonated forms in our
body.

This makes it useful to have in the active site

of a protein to stabilize or destabilize a
substrate.
Proline & glycine (α–helix breakers)

Proline: has a secondary amine (amino) group,

since the side chain loops round and forms a 2nd
bond with the alpha nitrogen.
• Primary amines: NHHR
• Secondary amines: NHRR’

Glycine: The side chain of glycine has 2 hydrogens,

either coming towards or away from you.
Therefore, alpha carbon is achiral, unlike the rest
of the amino acids which are chiral and have
optical activity.

It is considered very flexible (lots of free rotation)

due to the hydrogen present in its side chain.

These 2 amino acids are grouped together due to their role in disrupting the α-helix secondary
protein structure (see diagram above)

They introduce kinks in the helical structure, they are referred to as α–helix breakers

Cysteine
Cysteine contains a thiol group (-SH).

If in close proximity with another thiol, cysteines

can form a bond between the two Sulphur atoms
called a disulfide bridge.

Middle of the diagram:

The 2 cysteines of the thiol side chains are in a
reduced form (most likely to be found in reducing
environments, ex: intracellular).

RHS of the diagram:

The 2 cysteines of the thiol side chains are in an
oxidized form (most likely to be found in an oxidizing environment ex: extracellular)

Oxidization is loss, and when you ditch the hydrogens, their electrons go with them, and therefore
you lose their electrons. Thus, S-S form is oxidized form, while S-H and S-H form is reduced form.

The 2 hydrogens circled in green will be lost (oxidation) and we will see the formation of a disulfide
bridge.
To remember which environment is which, think: antioxidants exist within the cell, which stifle any
oxidizing reactions, therefore the inside of the cell must be reducing.
Amino acid structure

An amino acid has an alpha carbon between it’s amino group on the left side and its
carboxyl group on the right. On this alpha carbon you also find a Hydrogen and an R
group. This alpha carbon is a chiral center for all amino acids except for glycine
since it’s R group is an H making the amino acid achiral.

Reading Fischer projections:

Think: Solid bowtie, striped tie

L and D configurations are enantiomers.

To distinguish, just look at the amino group (NH2)

• In the L configuration, the amino group is on the
left
• In the D configuration, the amino group is on the
right.

* The L-configuration of AA is what we find in our proteins, cells, and body *

Isoelectric point and zwitterionns

Isoelectric point (pI) – point along the pH scale at which molecule is in a neutral form with zero
charge. Knowing pI, we can predict if amino acid is charged or not at a given pH.

Zwitterion – A molecule that has both positive and negative charge(s)

present, but a net charge of 0.

Low pH
Since there is an excess of protons (H+), the carboxylic group (COO–)
would gain a proton (COOH), we would have a net positive charge
since the NH3 remains positive. The molecule is then positive 1 (+1).

High pH
Since there is an excess of hydroxide ions (OH-), the amino group (NH3+) will be deprotonated and will
have a neutral charge (NH2). The carboxylic group will also be deprotonated at this point and will
have a negative charge, which gives us a net negative charge of -1

To find the exact pH where we find the zwitterion, we take the average pKa of the carboxylic and
amino functional groups.

The pKa varies between different amino acids, however:

• pKa1 (pKa of carboxylic acid group) = 2 on average
• pKa2 (pKa of amino group) = 9 on average
• Thus, pI = 5.5 on average
Classification of amino acids

They are classified according to: - charge

- H bonding ability
- acidic, neutral, or basic

1st group: non-polar/hydrophobic

There are 2 subgroups: alkyls and aromatics
All are neutral

2nd group: polar/hydrophilic

There are 3 subgroups: neutral, acidic and basic

Note – tyrosine can also be considered aromatic (since it has an aromatic ring)

Aspartic acid, glutamic acid – protonated form.

Aspartate, glutamate – amino acid form (anion/negative charge: proton has been donated)
Conformational stability: protein folding and denaturation

Protein conformation – a protein’s folded, 3D structure – active form

Denatured – an unfolded protein – inactive form

Solvation shell – a layer of solvent that surrounds a protein, providing a

force that helps to stabilize its conformation.
ex. a protein is positively charged on the exterior residues, and surrounding
it we have the water molecules positioned so that the oxygen (partial
negative charge) point towards (attracted to) the positive charge on surface
of the protein. The electronegative oxygen atoms are stabilizing the
positively charged amino acid.

The conformational stability is also affected by:

a) temperature: destroys 2°,3° and 4° structure. 1° structured is still preserved
b) pH: changing surrounding pH = disrupt ionic bonds
c) adding chemical denaturants: disrupts hydrogen bonding, destroying 2°, 3°, & 4° structure.
d) adding enzymes: breaks down all H bonds, they take the linear polypeptide chain and
bonds are broken into individual amino acids (proteases)

The structure and function of globular proteins (article)

Information included in article that has not be stated before:

Laws of thermodynamics maximize the free movement of water molecules at the molecular level:
• When a protein is stretched out (i.e. isn’t folded up into a secondary and tertiary structure),
the freedom of movement for the water in the surrounding environment is limited.
• ‘Crumpling’ proteins up into specific tertiary or quaternary structures maximizes the freedom
for water molecules to move.
o This explains why the upper level structures are ‘inclined’ to fold as such.
o
Native confirmation – correct, functional, active, three-dimensional, folded protein
• Some diseases are caused by errors in protein structure
o Anything that changes a protein from its native conformation decreases or destroys its
effectiveness.
o ex. sickle cell anemia – genetic mutation alters the shape of Hb molecules, causing
proteins to aggregate together in clumps.
o ex. fatal familial sleeping sickness – permanent, incurable, and ultimately deadly
insomnia, caused by a mutation that leads to a malformation of a protein called the
major prion protein.

Gene therapy seeks to fix errors in protein structure at the source

o Gene editing techniques such as CRISPR-cas9 allow scientists to cut and paste DNA sequences
into the genome of living organisms.
 o In this way we can (in theory) identify and replace mutated portions of a gene coding for a
misshapen protein, allowing us to ‘fix the problem at its source’ by changing the instructions
that specify the AA sequence of the protein.
o Given the central role of structure for the proper function of proteins, one might wonder if
there have been any attempts to cure diseases of protein structure by prompting the body to
produce properly-shaped versions.

Non-enzymatic protein function

Proteins can bind various biomolecules specifically and tightly

2 main classes (not all proteins are either or they can have the characteristics of both):
a) enzymatic: catalyzes reactions (ex: DNA polymerase, amylase)
b) non-enzymatic: 4 sub-classes as follows:

Non-enzymatic proteins:
1) Receptors/Ion Channels
Receptor: protein that binds or receives a signaling molecule
To the right, we have bilayer drawn in red lines, the receptor
protein in blue which binds the signaling molecule in green (aka
ligand) which will induce a chemical response in the cell.
In the figure, we have our ligand insulin. In response to an
increase in blood glucose, the pancreas releases this insulin
binding to the receptor and leads to a cascade of signals within the cells which allows it to accept the
glucose into the cell.
In yellow, we have an ion channel that spans the bilayer acting as a pore or channel which lets certain
ions enter or exit the cell.

2) Transport proteins
Responsible for binding small molecules and transporting them to other locations in a multicellular
organism.

Must have high affinity for ligand when ligand is

present in high concentration (to collect the
ligand), and low affinity for ligand when ligand is
present in low concentration (to deposit the
ligand)

Ex. Hb has a high affinity for O2 in the lungs where O2 concentration is high (acts to ‘load up’ the Hb),
while Hb has a low affinity for O2 in the tissues where O2 concentration is lower (acts to ‘drop off’ the
O2 at the tissues where we need it).
3) Motor proteins
Crucial for cellular motility:
-myosin: specifically, for generating forces exerted by
contracting muscles
-kinesin: intracellular transport
-dynein: intracellular transport, but also plays a role in
motility of cilia.

Mutation in dynein → primary ciliary dyskinesia → dysfunction of cilia along the respiratory tract →
decreased in mucous clearance → pneumonia or bronchitis.

4) Antibodies
Protein components of the adaptive immune system whore purpose is
to find foreign antigens and target them for destruction. An antigen is
essentially just the antibody’s particular ligand.
The antibody acts as a red flag of the immune system letting us know
that the foreign body is not supposed to be here.
The antibody’s affinity for its target antigen is extraordinarily high.
Alpha-carbon chemistry
Terminology notes:
o Alpha carbon (Cα) is just the first carbon atom that attaches to the functional group.

o Nucleophile = “nucleus loving” or “positive-charge loving”

o A nucleophile provides a pair of electrons to form a new covalent bond with a
positively charged molecule.

o Electrophile = “electron loving” or “negative-charge loving”

o An electrophile accepts a pair of electrons to form a new covalent bond with a
negatively charged molecule.
Aldol Reactions in Metabolism (article)

Aldol Reactions – Chemistry & Mechanism

Aldol reactions occur on either aldehydes or ketones.

Aldol addition reaction:

Step 1: Nucleophilic attack of an α-proton by a base generates an “enolate” carbanion.

Step 2: Newly formed enolate nucleophilically attacks the at the electrophilic carbonyl carbon of
a second molecule of aldehyde or ketone.

Step 3: Protonation of the product formed in Step 2 forms the aldol product

Aldol condensation reaction:

If heat is applied then an irreversible fourth step can take place, making the reaction an aldol
condensation reaction instead.

Step 4: A dehydration step (loss of water molecule) yields a αβ-unsaturated aldehyde or ketone.

Although aldol reactions can be base-catalyzed or acid-catalyzed,

we will focus on base-catalyzed aldol reactions (presence of OH– from the get-go)
Example: acetaldehyde (the simplest aldehyde – CH3CHO)

Step 1: “Nucleophilic attack of an α-proton by a base generates an “enolate” carbanion.”

Abstraction of an α-proton (a hydrogen attached to the Cα) from the Cα (first carbon attached
to the functional group) by a base forms the enolate ion (which is resonance stabilized – not
shown)

Step 2: “Newly formed enolate nucleophilically attacks the at the electrophilic carbonyl carbon of
a second molecule of aldehyde or ketone.” (aldehyde shown in this case)

Step 3: “Protonation of the product formed in Step 2 forms the aldol product”
As you can see, the newly formed product contains both an aldehyde and an alcohol functional
group, thus the name 'aldol reaction'.

An aldol reaction always leads to the generation of a new carbon-carbon bond.

–––

If this reaction is taking place under conditions of elevated temperatures, then an additional step
will take place, making the reaction an aldol condensation reaction

Step 4: A dehydration step yields a αβ-unsaturated aldehyde or ketone.

NOTE: although it is not shown in the mechanism above, the OH that is to leave first gets
protonated to become a positively charged water molecule, which is now an excellent leaving
group and will leave (hence: dehydration step)

–––

Aldol Reactions – Metabolism

Adolases – the class of enzyme that catalyzes aldol reactions (in both directions, i.e. aldol
reactions and retro-aldol reactions)

Aldol reactions are used in many reactions during metabolism:

o TCA cycle:
o OAA + Acetyl-CoA → (S)-Citryl-CoA in first step of TCA cycle
o Gluconeogenesis (sugar synthesis):
o GAP + DHAP → Fructose 1,6-BP

Retro-aldol reactions are also important during metabolism:

• Glycolysis (sugar breakdown):
o Fructose 1,6-BP → GAP + DHAP
Example 1: TCA cycle Acetyl-CoA + OAA → (S)-Citryl-CoA

Acetyl-CoA is the starting material (nucleophilic partner), which is actually a thioester rather
than a ketone or aldehyde.

Step 1: Base (B:) abstracts an α-proton to form the Acetyl CoA enolate intermediate.

Step 2: The enolate attacks the electrophilic carbonyl carbon of oxaloacetate ion.
Step 3: Protonation of the above product to form the final product, (S)-Citryl-CoA.

-> Generation of a new carbon-carbon bond

-> Generation of a new stereo-center (which happens to have an ‘S’ configuration)
• In biochemistry, the stereocenter is created by the specific stereo-requirements of the
enzyme’s active site at which the reaction takes place

Example 2: Gluconeogenesis GAP + DHAP ––1,6-BP aldolase→ Fructose-1,6-BP

Glyceraldehyde-3-phosphate (GAP) 3-carbon containing sugar (aldehyde)

+
Dihydroxyacetone phosphate (DHAP) 3-carbon containing sugar (ketone)
=
Fructose 1,6-bisphosphate (Frutcose-1,6-BP) 6-carbon product (aldol)

1,6-bisphosphate aldolase is a 'Class II' aldolase, in which a metal cation – generally Zn2+ – is
bound in the active site of the enzyme.
• This helps to stabilize the negative charge of the enolate intermediate formed in Step 1.

Net reaction:
Step 1: An (α-proton) of DHAP is abstracted by a base (B:), leading to the formation of an enolate
intermediate of DHAP.

The above carbanion enolate intermediate is stabilized by resonance, and the negative charge on
the enolate is further stabilized by the aldolase enzyme-bound zinc cation (Zn2+) as shown
below.

Step 2: The nucleophilic attack of the enolate carbanion on the electrophilic carbonyl carbon of
glyceraldehyde-3-phosphate (GAP).
Step 3: Protonation of the product formed in step 2 to form the final product, fructose 1,6-
bisphosphate. Source of proton donor is water (H2O).

-> Generation of a new carbon-carbon bond

-> Generation of a new stereo-center (which happens to have an ‘R’ configuration this time)
• This enzyme-catalyzed reaction, not surprisingly, is completely stereospecific:
o The DHAP substrate is positioned in the active site such that the attack of the GAP
carbonyl group, leads to an R configuration at the new stereocenter every time

–––
Aldol reactions are highly reversible in nature because in most cases, the energy levels of
reactants and products are not very different.

Thus, depending on the metabolic conditions, aldolases can also catalyze retro-aldol reactions
(i.e. the reverse of aldol reactions, in which a carbon-carbon bond is broken to form two
molecules).
Fructose 1,6-bisphosphate aldolase enzyme catalyzes the reaction in both directions, and is
therefore not only involved in the gluconeogenesis pathway (sugar synthesis) but also the
glycolysis (sugar breakdown) pathway:
• Retro-aldol cleavage of fructose 1,6-bisphosphate into DHAP and GAP as shown below.

Example: Glycolysis Fructose-1,6-BP ––1,6-BP aldolase→ GAP + DHAP

Mechanism of the retro-aldol reaction:

Step 1: Abstraction of a proton by base (B:). Notice how the electrons move around leading to
breakage of the carbon-carbon bond, generating glyceraldehyde-3-phosphate (GAP). The enolate
ion serves as the leaving group as depicted below.
The enolate intermediate is stabilized by resonance, as shown below. The negative charge on the
enolate is further stabilized by the Zn2+ bound to the active site of fructose 1,6-bisphosphate
aldolase enzyme.

Step 2: Protonation of the enolate carbanion resulting in the formation of dihydroxyacetone

phosphate (DHAP).
Keto-enol tautomerization

Side note: This is a reaction that involves a ketone, but an aldehyde can undergo
same reaction

This lecture focuses on ketone -> enol reaction (keto-enol tautomerization)

Process:
• At the start, there is a ketone floating around in water.
• In water, we know that there is some concentration of hydronium (H3O+)
• The oxygen from the ketone takes away one proton from the hydronium ion, producing water
as a byproduct.
• Since the oxygen is sharing its electron now, it now has a positive charge.
• As a result, it is resonance stabilized (in the way shown in square brackets).
• In the resonance form shown at the bottom, there is a carbocation.
• The water (which was a byproduct in the initial reaction) can then take the proton (shown in
green) off of the molecule, leaving some electrons free to stabilize the structure by forming a
double bond between two of the carbons.
• This new molecule is called an enol, named as such because it is both an alkene (C=C) and an
alcohol (-OH)

Terms:
• The ketone and enol forms of this molecules are tautomers of each other (same molecular
formula but different connectivity).
• The mechanism is therefore called a tautomerization.

Side note: The ketone is the more stable of the two (since the C=O double bond is stronger).
Enolate formation from aldehydes

We’ve seen before how to form the enolate anion (that intermediate, resonance stabilized structure
in the aldol reaction) from an aldehyde in the presence of a base.

Note the equilibrium arrows between the aldehyde and the enolate.
• We can use the pKa values of the acids (the original aldehyde and the H:B formed in the
reaction) to determine which direction equilibrium lies towards
o Reactants (aldehyde + B) ↔ Products (enolate anion + H:B)

Example 1:

Thus, there will be mostly aldehyde (reactants) present at equilibrium, with only some enolate anions

Another way to reach this conclusion: equilibrium favors the formation of the weaker acid, and
since the aldehyde has a higher pKa, it is the weaker acid of the two.
Example 2:

Enolate formation from ketones

Another way to reach this conclusion: equilibrium favors the formation of the weaker acid, and
since the H:B has a higher pKa (and the conjugate acid of a strong base is a weak acid), it is the
weaker acid of the two.
Comparing pKa values of Aldehydes and Ketones (in general)
• Ketones generally have higher pKa values (weaker acid) than aldehydes
• Equilibrium is more likely to lean towards the side that has a weaker acid (higher pKa)

• Ketones
o The methyl group in ketones (ex: acetone) donates electron density to stabilize the
partial positive charge on the carbonyl carbon.
o Since the positive charge is stabilized, acetone feels less inclined donate a proton to
the base, so equilibrium will generally stay further to the left (towards the weaker acid
aka higher pkA)
• Aldehydes
o There isn’t the same electron density present to stabilize the partial positive charge of
the carbonyl carbon.
o Since the aldehyde molecule isn’t quite as happy, the enolate anion is more likely to
form.
o The aldehyde is therefore more acidic (lower pKa)

Very specific case where we have a very acidic ketone:

• Though there are three Cα, the Cα in the middle has the most acidic protons (pKa of protons =
9) (think of it like a combined effect from being influenced by a ketone from either side).
 • Since the enolate anion (the conjugate base) is very well stabilized by resonance structures, it
is more likely to form. This means that the ketone is very acidic and is likely to donate its
protons (meaning that its pKa is low and equilibrium lies to the right)

Summary:
• Aldehydes are generally more acidic (lower pKa) than ketones
o Why? No electron density to stabilize the partial positive charge on the carbonyl
carbon, so the aldehyde is fundamentally less stable (more reactive, more likely to
donate a proton)
• Equilibrium favors the formation of the weaker acid, and thus will often lie towards the side
that has the acid with a higher pKa value.
• pKeq = pKaacid left – pKaacid right
• Keq = 10–pK eq
Kinetic and thermodynamic enolates

Kinetic enolate:

LDA is a strong base but is bulky, and will therefore ‘approach’ the reactant (aldehyde or ketone)
from the least sterically hindered side (if performed under cold temperature rx conditions)

In this case the least sterically-hindered side is the RHS with the methyl group, since the LHS has a
methyl group + an R-group. Thus, LDA will pull off an α-proton from the RHS.

The product in this case is the kinetic enolate, meaning that it is the product that forms fastest
• It forms the fastest due to
o (a) the use of a sterically hindered base at low temperatures (e.g. LDA at –78 °c)
o (b) probability, since there are 3 α-protons to choose from on the RHS Cα but only 2 α-
protons to choose from on the LHS Cα

Thermodynamic enolate:

Hydride anion (H–) is used as a base instead:

The product in this case is the thermodynamic enolate, meaning that it is the product that is most
stable (see below)
Comparing the stability of the kinetic vs. thermodynamic enolate ions:

The more substituted the double bond of a C=C bond, the more stable the bond (a substituent is any
atom or group of atoms that replaces a hydrogen atom).
• In the case above, the double bond of the thermodynamic enolate is more substituted (R, O,
and C) than the double bond of the kinetic enolate (C-R, O)
• Thus, although the kinetic enolate forms faster, the thermodynamic enolate is more stable.

You can control whether the kinetic or thermodynamic enolate ion forms depending on
which base you use (LDA vs. H–) and reaction conditions (cold temperature)
Aldol condensation (simple, i.e. reactants are the same molecule)

Aldol addition (from before)

• Aldol is the product of this reaction which has both an aldehyde and alcohol functional group.

Aldol condensation
• Addition of heat makes the reaction go one step further to become an aldol condensation
reaction instead, which starts with the aldol (that was made in the previous reaction) and
forms an enal

The second hydrogen that is attacked in this extension of the reaction is just another α-proton from
the same Cα that the original α-proton was pulled from.
Example 2 (formation of an enone – alkene (double bond) and ketone characteristics)
Aldol condensation (mixed/crossed, i.e. reactants are different molecules)

Example 1:

Since the LHS structure has no Cα, it won’t be able to form an enolate anion

Example 2:

Now we have a choice of Cα between the molecules, so how do we know which the initial
deprotonation step will occur on?

Recall: the protons between two carbonyls of the RHS structure are the most acidic and will
deprotonate very readily, because the enolate anion that forms is very stable due to its multiple
forms of resonance stabilization.
Aldol condensation (mixed/crossed, and directed using a lithium enolate)

Imagine carbonyl compounds A and B.

• If you just mix them together with a base, you will get a mixture of four different aldols:
o A-A, A-B, B-A, and B-B.
• Your maximum yield would be about 25%.
• It is much better to form the enolate of one compound first and then add it to the second
carbonyl compound (directed aldol reaction)
o This step-wise addition prevents the enolate intermediates of both different carbonyl
compounds from forming.

Example:

LDA is a strong, bulky base that will form the kinetic enolate (i.e. it will take an α-proton from the
less-sterically-hindered Cα)

It wasn’t mentioned before in our talks with LDA, but what actually happens is a cyclic mechanism
(O forms a bond with Li, N forms a bond with H)

Note, this is the opposite resonance structure for enolates than we are used to seeing. For visualization, imagine that the
electrons that formed the double in the enolate are instead on the Cα as lone electrons such that the Cα– bears the
negative charge, and there is a C=O bond instead such that the oxygen no longer bears the negative charge.

We can now be sure that the kinetic enolate (lithium enolate) of the ketone has formed, while none
of the thermodynamic enolate of the ketone or any enolate of the aldehyde has formed.
• This stepwise manner allows us to get predictable aldol product from the reaction when we
next add the other reactant, rather than us getting a mix of products depending on whether
the Cα on the left or right was deprotonated by the base in the first step, or whether the Cα
on the ketone or aldehyde was deprotonated.
Now if we progress with the aldol condensation, we can reach our final product. This follows a
slightly different mechanism, since we are in the presence of an acid, so the leaving group first
becomes water and then leaves, followed by the step involving the removal of the second alpha-
proton by a base with the subsequent formation of the double bond

Summary:
Directed aldol reactions follow the same idea except the particular enolate intermediate that will
form is driven by a stepwise manner of adding the compounds (the lithium enolate intermediate of
the first carbonyl compound is formed first and then the second carbonyl compound is added, such
that only the enolate of one of the starting reactants is formed.

This example also has a few additional details on the use of LDA to get a particular enolate, the
movement of Li, and how OH is not actually a good leaving group until it gets protonated to become
a positively charged water molecule, whereby it can now leave – a step that has been skipped in past
examples for simplicity but is an important note)
Retrosynthesis via the Retro-aldol reaction

Retro-aldol reaction (start with the product of the aldol condensation reaction, and work backwards
to reach the two starting reactants of aldehydes and/or ketones)

If you are starting with the substituted product (i.e. the product of the 4-step aldol condensation
reaction), you can think of it like cutting your double bond, taking a water molecule and splitting it
into its pieces, and then adding the two hydrogen ‘pieces’ onto the Cα, and the oxygen ‘piece’ onto
the Cβ:
If starting with the product of the 3-step aldol addition reaction, the only change that really happens
is that the proton of the alcohol group is removed by a base and the C=O bond of the second
carbonyl compound reforms, and the α-proton of the first carbonyl group that is lost in the first step
is re-added because the carbanion whips one off of water or some proton source.

After using these thought processes to determine the original carbonyl compounds that were used to
create the final product, we can predict the work-up that was used to produce the product in the first
place:

Directed, since it was a mixed/crossed aldol reaction (i.e. two different starting carbonyl compounds)
Intramolecular aldol condensation

Example 1:

Example 2:

Cα3 and Cα4 give a product with too much angle strain.

Since KOH is a base that will favor the thermodynamic product (most substituted product), Cα6 is a
better option than Cα1
Aldehydes and Ketones

Nomenclature of aldehydes and ketones

Aldehydes
• Replace the –e at the end of the alkane or alkene name with the suffix –al.

• Carbonyl carbons of aldehydes have priority over things like double bonds, alkyl groups, and
halogens, such that they carbonyl carbon of the aldehyde gets assigned the number 1, so no
need to label the position of the aldehyde, since we already know it will be one

• The ‘al’ becomes ‘dial’ if two aldehyde groups are present

 • If the aldehyde is attached to a ring, the suffix carbaldehyde is used instead.

Ketones
• Replace the –e at the end of the alkane or alkene name with suffix –one.

• When naming ketones by their common names (or old name), the substituent groups (i.e.
the two alkyl groups, denoted R) are named alphabetically, followed by ketone.

• It’s also important to specify where the ketone is

• Carbonyl carbons of ketones have priority over things like double bonds, alkyl (R) groups, and
halogens, such that they carbonyl carbon of the ketone gets assigned the lowest number

• The ‘one’ becomes ‘dione’ if two ketone groups are present

• Use either the prefix oxo– or keto– when ketones are named as substituents (ex. when they
are present in the same molecule as aldehydes, since aldehydes have priority over ketones),
Physical properties (BP and Solubility) of aldehydes and ketones

Boiling points
• Boiling point is dependent on the intermolecular forces (forces between molecules) that
are at play
• Alcohols
o Hydrogen bonding (a type of dipole-dipole interaction whereby a H that is
connected to F,O, or N interacts with F, O, or N on another molecule) is the
strongest type of intermolecular force, so it takes a lot of energy to pull apart
molecules that are participating in hydrogen bonding with each other.
o Thus, the BP of alcohol (ex. 2-pronanol shown below) is very high (i.e. it requires a
lot of energy to separate the hydrogen-bonded molecules)

• Aldehydes and Ketones

o Ketones also have dipole-dipole interactions, but they are not as strong because
they are not hydrogen-bonding, they are simply the dipole-dipole interaction
between the partial negative of the O and the partial positive of the carbonyl C.
o Thus, the BP of ketones is a little lower, since not quite as much energy is required
to separate the molecules out

• Alkanes
o No dipole-dipole interactions, only London dispersion forces (which exist between
all molecules) so very easy to separate (i.e. very low BP, very low temperature
required to separate the molecules)

Highest BP ––– Alcohols > Aldehydes & Ketones > Alkanes ––– Lowest BP
Solubility in water
• In water, aldehydes and ketones can participate in hydrogen-bonding with the molecules
of water and are thus soluble in water (also, polar-likes-polar, which is another hint that
they would be soluble in water)
• However – as you increase the chain length of the alkyl (R) groups, the non-polar
character of the molecule increases, and the now-less-polar molecule will be less soluble
in water.
o Thus, small aldehydes/ketones are water-soluble, but long-chain
aldehyde/ketones are not soluble in water.

Reactivity of aldehydes and ketones

Polarization of the carbonyl

• Since oxygen is so EN, it draws some of the electron density away from the carbonyl
carbon, giving partial charges (O δ–, and C δ+).
• However, alkyl group(s) (R) donates some electron density to the carbonyl carbon
(R C) to partially stabilize the δ+ of the carbonyl carbon
o Since ketones have two alkyl (R) groups, the carbonyl carbon is even more
stabilized, making ketones inherently less polarized and more stable than
aldehydes, while aldehydes are inherently more polarized and less stable than
ketones (i.e. the δ+ of the carbonyl carbon is a little more in aldehydes).

Steric numbers of the carbonyl

• Steric number = # sigma bonds + # lone pair electrons
 • Steric number (carbonyl carbon) = 3 sigma bonds + 0 lone pair electrons = 3
o Recall: double bonds are made up of 1 sigma, 1 pi bond
o Thus this carbonyl carbon has 3 sp2 hybrid orbitals and 1 unhybridized p orbital
• Steric number (oxygen) = 1 sigma bonds + 2 lone pair electrons = 3
o Thus this oxygen has 3 sp2 hybrid orbitals and 1 unhybridized p orbital
• The pi bond comes from the side-by-side overlap of the p-orbitals.
• The sp2 hybridization means that the geometry is trigonal planar, so the atoms lie on the
same plane, and thus the bond angle is close to 120°

Combining the idea of geometry and polarization

Aldehydes are inherently more reactive than ketones:

• Aldehydes are more polarized than ketones – since the δ+ on the carbonyl carbon of an
aldehyde is a little more positive, it is more likely to be engaged upon by a nucleophilic
attack
• Aldehydes are less sterically hindered than ketones – since they only have one alkyl group,
its ‘easier’ for a nucleophile to engage in a reaction with the aldehyde as compared to the
ketone.

––––––
Terminology & broad reaction introduction for the coming few lectures:
Formation of hydrates (gem diols)

In the presence of water, aldehydes and ketones (not shown) react to form geminal diols (1,1-
diols).

The nucleophilic oxygen of water attacks the electrophilic carbonyl carbon.

Examples:

Aldehydes and ketones can be made more reactive by adding something else that withdraws
even more electron density away from the carbonyl carbon, (ex. a halogen like Cl), such that δ+
becomes δ++
Formation of hemiacetals and hemiketals

The mechanism for aldehyde / ketone -> hemiacetal / hemiketal is the same as the mechanism
for aldehyde / ketone -> hydrate (gem diol)
• The only difference here is that an alcohol acts as the nucleophile that attacks the
aldehyde / ketone, rather than water acting as the nucleophile.

Hemiacetals and hemiketals can be recognized by the retention of one hydroxyl group.

The formation of hemiacetals is usually not favored (i.e. equilibrium lies to the left):

…unless the hemiacetal is more stable (e.g. hemiacetals in the form of 5- or 6-carbon rings,
formed via intramolecular hemiacetal formation):
5- and 6-carbon ringed hemiacetals are important for carbohydrate chemistry:

This “halfway” step (hence the hemi– prefix) is the endpoint in basic conditions. When two
equivalents of alcohol are added, the reaction proceeds to completion, resulting in the formation
of an acetal or ketal (coming up in a future lecture)

1 OH group 0 OH groups
Acid and base catalyzed formation of hydrates and hemiacetals

Acid catalyzed reactions – work by making the carbonyl carbon more electrophilic, which makes it
more reactive in a nucleophilic addition reaction
• First step is protonation of the carbonyl oxygen
• The resonance structure of this has a very electrophilic carbonyl carbon, which sets up
conditions that really drive the formation of a hydrate or hemiacetal/hemiketal in this
nucleophilic addition reaction
• ex: Aldehyde or Ketone ––H2O as Nu:, acid as catalyst ––> Hydrate

• ex: Aldehyde or Ketone ––ROH as Nu:, acid as catalyst ––> Hemiacetal or Hemiketal
o (not shown)
Base catalyzed reactions – work by making the nucleophile more nucleophilic, which makes it more
reactive in the nucleophilic addition reaction
• First step is deprotonation of the nucleophile
• The deprotonated nucleophile is now even more nucleophilic, which sets up conditions that
really drive the formation of the hydrate or hemiacetal/hemiketal in this nucleophilic addition
reaction
• ex: Aldehyde or Ketone ––Nu: was H2O but is now OH– thanks to base catalyst ––> Hydrate

• ex: Aldehyde or Ketone ––Nu: was ROH but is now RO– thanks to base catalyst ––>
Hemiacetal or Hemiketal
o (not shown)

Summary
• Either an acid or a base can be used to catalyze the nucleophilic addition reactions that are
responsible for Aldehyde/Ketone -> Hydrate and Aldehyde/Ketone -> Hemiacetal/Hemiketal
• Acid catalyzed reactions – work by making the carbonyl carbon more electrophilic, which
makes it more reactive in a nucleophilic addition reaction
• Base catalyzed reactions – work by making the nucleophile more nucleophilic, which makes it
more reactive in the nucleophilic addition reaction
Formation of acetals

Hemiacetal/Hemiketal (1 OH group) –ROH excess, acid environment –> Acetal/Ketal (0 OH groups)

+ H2O

To shift equilibrium to the right, you could (a) remove the water as it forms, (b) increase
concentration of one of the reactants
B:
↓
Examples 2 and 3:

Formation of a cyclic acetal in the second example because of the diol reactant leading to an
intramolecular nucleophilic attack (middle step)
Acetals as protecting groups

Divergence:
Carboxylic acids can usually be reduced to alcohols using (1) LiAH4 and (2) H3O (a source of protons)
in a reaction like the ones below

However, in the following reaction, this won’t work, because LiAlH4 will also reduce the ketone to
form a secondary alcohol.
Thus, the ketone needs protecting first, and this protection comes by forming an acetal which will act
as a protecting group
Formation of thioacetals

Thioacetal formation is completely analogous to the formation of an acetal, but instead of using an
alcohol (ROH) you use a thiol (RSH) (sulfur in the place of oxygen)

Thioacetals have an additional reaction that they undergo, so can be useful in some cases:

Example: goal is to get the molecule on the right from the molecule on the left

Mechanism:
Raney Nickel uses
Formation of imines and enamines

Nitrogen and nitrogen-based functional groups act as good nucleophiles due to the lone pair of
electrons on nitrogen, and react readily with the electrophilic carbonyls of aldehydes and
ketones.

Y–NH2 (Y = H is just ammonia, NH3) (Y can be other groups too) adds to the carbonyl carbon
atom and produces water, producing an imine (C=N)
• This is an example of a nucleophilic substitution/ condensation reaction.
• Removing water as it is formed shifts equilibrium to the right

Two ways to start the mechanism’

• First way is involves protonation of the carbonyl oxygen, which makes the carbonyl
carbon more electrophilic (imagine the resonance structure if it helps). Electrophilic
carbonyl is attached by the nucleophilic nitrogen.
o (1) Protonation of oxygen, (2) Nucleophilic attack by nitrogen
• Second way is direct attack by the nucleophilic nitrogen on the δ+ carbonyl carbon,
followed by a protonation step.
o (1) Nucleophilic attack by nitgrogen, (2) Protonation of oxygen
• Both ways end up getting to the same intermediate
Starting with the intermediate on the RHS of the last diagram:
• Base strips a proton off of nitrogen to alleviate the positive charge (forming a
carbinolamine)
• –OH group gets protonated, making H2O (which acts as a leaving group).
• When water leaves, the lone pair of electrons from nitrogen form a N=C double bond such
that nitrogen bears the positive charge (rather than carbon)
o This intermediate is now called the iminium ion
• Deprotonation of the iminium ion gives out final imine product

Reverse reaction (imine hydrolysis):

Since water is a product in the original water, adding water drives the reaction towards the left (i.e.
the reverse reaction) forming our ketone (or aldehyde) and primary amine once again
Formation of imine – Example:

If you start with a 2° amine as a reactant, then the reaction is going to get ‘stuck’ in the
penultimate step (see asterisks in the diagram above and below), whereby the C=N bond has
formed and the nitrogen is bearing a positive charge. However, now there is no hydrogen on the
N to deprotonate, so instead a tautomerization reaction must occur, whereby a hydrogen
elsewhere on the molecule is taken and the electrons move through the molecule to balance
charges, like so:
This is a tautomerization (a lot like the keto-enol tautomerization of carbonyl compounds that
we saw before) that results in the formation of an enamine
• ene = double bond
• amine = a nitrogen containing group
• See how the proton from an adjacent carbon is pulled off and the spare electrons are used
to fix the charge issues

Formation of oximes and hydrazones

Oxime formation
• Same reaction as imine formation, but just bearing in mind that the Y group is OH now
• Oximes are more stable than imines, because they are well resonance stabilized (see below)
which allows for delocalization of some of the electrons
• Why doesn’t the O act as a nucleophile in competition with N? It does, but it’s a dead-end
processes since it gives a reversible formation of a hemiketal, whereas the reaction with N
forms the oxime in an essentially irreversible process
Example 2:

Formation of stereoisomers

Hydrazone formation
• Same reaction as imine formation, but just bearing in mind that the Y group is NHR’’ now:
• Hydrozones are also most stable than imines (due to resonance stabilization)

Example 2:
Addition of carbon nucleophiles to aldehydes and ketones

KCN has the carbon nucleophile

(since it actually looks like this ↓)

Carbon-carbon bond formed. Once you have that –CN group (‘cyano’ group), it can be turned into
other functional groups, which is why this reaction is useful for a synthesis.

Mechanism:

Example:
Another type of carbon nucleophile – R’’-MgX or R’’-LiX (organo metallics)
• Carbon is more EN than Mg or Li, so electrons are polarized towards the carbon, giving the
carbon a δ– and therefore making it a nucleophile
• Side note: R’’-MgX is a Grignard reagent (comprised of an akyl group, Mg, and Cl, Bl, or I as a
halogen)

Example (aldehyde)
Example (ketone)

Summary of carbons as nucleophiles:

• KCN
• R’’-MgX (organo metallic)

Formation of alcohols using hydride reducing agents

Aldehydes and ketones can also undergo reduction to form alcohols.

This is often performed with hydride reagents.

The most common of these are lithium aluminum hydride (LiAlH4), and sodium
borohydride (NaBH4), which is often used when milder conditions are needed (since it is less
reactive)
Example:

LiAlH4 works the in a similar way

Needs two steps to prevent:

Why does LiAlH4 need two steps but NaBH4 can be done all together?
• LiAlH4 is much more reactive the NaBH4. Why? Boron has an EN = 2, Lithium has an EN = 1.5,
so boron ‘wants’ the electrons in red more that Lithium does, meaning that its easier for
Lithium to give these electrons away, making it more reactive

NaBH4 is strong enough to reduce aldehydes to alcohols, but isn’t strong enough to mess with esters.
LiAlH4 however is strong enough to reduce both aldehydes and esters to alcohols (reduction of
esters plus a bunch of other functional groups will be explained in a later video – LiAlH4 is mad
reactive)
Oxidation of aldehydes using Tollens’ reagent

Side: How do you assign oxidation states to dot structures?

• Use EN to assign electrons in bonds to the most EN atom of the two, then count up
• Minus your count from the number of valence electrons that that atom has
• Example:

Aldehydes ––oxidation––> Carboxylic acid can be done using Tollen’s reagent

•
Tollen’s reagent consists of a source of silver ions (Ag+), a source of hydroxide ions (OH-),
and a source of NH3, which forms [Ag(NH3)2]+

Since the carbon is getting oxidized, something else must be getting reduced. In this case, it is the
Ag+ that is getting reduced (to Ag, which produces a silver mirror)
Example 2 – using glucose as your aldehyde:

O– would then be protonated

to form a carboxylic acid

NOTE: Tollen’s reagent is selective in that it only oxidizes aldehydes (doesn’t oxidize alcohols or
ketones).
• This is because it is a mild oxidizing agent
Any oxidizing agent stronger than PCC can perform this reaction.
Ex:
• Di-amine-silver (Ag(NH3)2)
• Potassium permanganate (KMnO4)
• Chromium trioxide (CrO3)
• Silver(I) oxide (Ag2O)
• Hydrogen peroxide (H2O2).

Cyclic hemiacetals and hemiketals

Intermolecular hemiacetal formation

The above reaction exemplifies the formation of an intermolecular hemiacetal. These are
intrinsically unstable and tend to favor the parent aldehyde.

Molecules which contain both an alcohol and a carbonyl group (aldehyde or ketone) can instead
undergo an intramolecular reaction to form a cyclic hemiacetal/hemiketal. These, on the
contrary, are more stable as compared to the intermolecular hemiacetals/hemiketals. Stability of
cyclic hemiacetals/hemiketals is highly dependent on the size of the ring, where 5 & 6
membered rings are generally favored.

Intramolecular hemiacetal formation

Intramolecular hemiacetal and hemiketal formation is commonly encountered in sugar
chemistry. Just to give you an example: in solution, ~ 99% of glucose exists in the cyclic
hemiacetal form and only 1% of glucose exists in the open form.

Cyclization of glucose to its hemiacetal form

Let’s first draw a molecule of glucose (C6H12O6). The simplest way to do so is by using the Fischer
Projection as shown below

Fischer projection of glucose highlighting its aldehyde group and hydroxyl group

Recall – glucose flips people off

Glucose has an aldehyde group and five hydroxyl groups, meaning that it can form an
intramolecular cyclic hemiacetal.
 Mechanism for the formation of hemiacetal glucose from its original open form

So why doesn’t the hydroxyl attached to C-4 react with the carbonyl group? Why does the
carbonyl group react with the hydroxyl attached to C-5? C-4 hydroxyl attacking the carbonyl
group will lead to the formation of a 5-membered ring, while the attack of C-5 hydroxyl at the
carbonyl group will generate a 6-membered ring (as shown in the above figure). In the case of
glucose, a 6-membered ring is thermodynamically more stable than a 5-membered ring, thus
favoring the formation of a 6-membered ring over a 5-membered ring.

Now let’s shift our focus to the hemiacetal of glucose (Haworth projection). If you notice this
cyclization process creates a new stereogenic center, C-1, which is referred to as the anomeric
carbon. Glucose can exist as an α or a β isomer, depending on whether the OH group attached to
the anomeric carbon (C-1) is on the same side as the CH2OH group or is on the opposite side.
These two forms are referred to as anomers of glucose.

Haworth projection and chair conformation

In aqueous solution, glucose exists in both the open and closed forms. These two forms always
exist in equilibrium. In the process of converting from closed to open form and then back to
closed form, the C-1→ C-2 bond rotates. This rotation produces either of the two anomers. We
term this phenomenon of opening of the ring, rotation of the C-1→ C-2 bond and the subsequent
closing of the ring as mutarotation. So as a result of mutarotation, both the α and β anomers are
present in equilibrium in solution. In the case of glucose, β anomer is more predominant than α
anomer. This may not be the case with all the monosaccharides.

Cyclization of fructose to its hemiketal form

Now let’s change gears and apply the same principles (as applied to glucose) to a molecule of
fructose. Fructose has a ketone group and five hydroxyl groups. So, fructose should also be able
to cyclize to form an intramolecular hemiketal.

Recall: fructose is like the ‘ketose version’ of glucose

There are in fact two ways in which a molecule of fructose can cyclize. The first is as illustrated
below

Here, as you can see, the hydroxyl attached to C-5 attacks the carbonyl group, yielding a 5-
membered ring (furanose form).

In the second scenario (as shown below), the hydroxyl attached to C-6 attacks the carbonyl
group, resulting in a 6-membered ring (pyranose form).
Alcohols and phenols

Alcohol Nomenclature

Alcohols are named in the IUPAC system by replacing the –e ending of the root alkane with the
ending –ol.

1°, 2°, 3° (just ask ‘how many carbons are attached to the carbon that the OH is attached to?)

Examples:

If the alcohol is the highest-priority functional group, the carbon atom attached to it receives the
lowest possible number.
When the alcohol is not the highest-priority group, it is named as a substituent, with the
prefix hydroxy–.

3-hydroxy-3methylbutanal

Stereochemistry involved:

Alcohol in a ring gets a cyclo- prefix

Two alcohols in the same molecule gets the suffix –diol instead of -ol
Aromatic alcohols (based off of a benzene ring) are called phenols.

The hydroxyl hydrogens of phenols are particularly acidic due to resonance within the phenol
ring.

Side note: When benzene rings contain two substituents, their relative positions must be
indicated. Two groups on adjacent carbons are called ortho–, or simply o–. Two groups
separated by a carbon are called meta–, or m–. Two groups on opposite sides of the ring are
called para–, or p–.

Ortho = straight, upright, right, correct (think ‘orthodox’)

Meta = after
Para = related (think penis)
Properties of Alcohols

Physical properties:

Since oxygen is very EN, there is a high degree of polarity in the O–H bond (the electronegative
oxygen atom pulls electron density away from the less electronegative hydrogen atom)

This polarity sets alcohols up for:

• Intermolecular hydrogen bonding:
o H-bonding is a very strong force which results in significantly higher MP and BP
compared to those of analogous hydrocarbons (ex. alkanes).
o Molecules with more than one hydroxyl group show greater degrees of hydrogen
bonding.
• High degree of water solubility.
o Ethanol (CH3CH2OH) is completely soluble in water (ex. beer is a mixture of water
and ethanol)
o The more carbons on your alkyl group of the alcohol molecule, the less soluble the
entire molecule will be due to the carbons being non-polar and hydrophobic.

Preparation of Alkoxides

Alkoxide – the conjugate base to an alcohol (i.e. alcohols are acidic if you use a strong
enough base)

Example:
Alternate way to form alkoxides using Group 1 Alkali Metals (M) (ex. Li, Na, K)

Example:

Biological oxidation of alcohols (redox reactions) (article)

The body processes alcohols through biological oxidation.

Recall: ethanol is completely soluble in water. When we drink a beer, the ethanol molecules quickly
absorb into our bloodstream via our stomach and SI. Once in the blood, ethanol moves all around the
body, rapidly affecting the brain and causing us to get drunk.

Metabolism of ethanol in the liver (2 step process):

Step 1:
Step 2:

Both steps are oxidation reactions, as you can see here:

This reaction only works with 1° or 2° alcohols
In the lab, Ethanol -> Acetic acid can be easily carried out by the addition of an oxidizing agent
such as in the presence of sulphuric acid.

However, in our bodies, this oxidation process is catalyzed by enzymes (see below) and
coenzymes instead:
• Coenzymes (NAD+ and NADH)
o NAD+ is the oxidizing agent, since it oxidizes the alcohol in the first step and the
aldehyde in the second step (while getting reduced to NADH itself)
• Enzymes (ADH1B and ALDH2)
o Alcohol dehydrogenase IB (ethanol ––ADH1B––> acetaldehyde)
o Alcohol dehydrogenase 2 (acetaldehyde ––ALDH2––> Acetic acid)

• This step of the reaction is reversible: ethanol can be reduced back to ethanol (whereby
NADH will be oxidized back into NAD+)
Acetaldehyde
• Acetaldehyde (the initial product formed) is toxic to our body (partially explains
hangovers) and so it is important that it gets oxidized to acetic acid as quickly as possible
(via the ALDH2 catalyzed reaction)
• Acetaldehyde is also a vasodilator, explaining why we get flushed when we drink alcohol.
o East-Asian people have a mutated ALDH2 gene, explaining why they get more
flushed when they drink!

NOTE:
• Not all alcohols can be converted into something harmless (such as acetic acid). For
example, methanol is extremely poisonous and can cause blindness after only 2 tbsp and
death among other symbols too.
• This is because the reaction goes methanol -> formaldehyde -> formic acid
• Both formaldehyde and formic acid are deadly, first attacking cells in the retina and then
the cells of other vital organs.

Biological redox reaction of phenols:

Oxidation of alcohols (+ examples)

PRIMARY ALCOHOL RXNS:

Jones Reagent (for oxidation of 1°&2° alcohols):

Pyridinium Chlorochromate (PCC) reagent – will stop the oxidation at the aldehyde (middle
step) instead of going to completion to form the carboxylic acid.

In both cases, the alpha carbon gets oxidized

while the chromium of the reagent gets reduced (chromium is the OA)
SECONDARY ALCOHOL RXNS:

With 2° alcohols a ketone is the only result. You can use EITHER Jones or PCC reagent and
will end up with same result.

3° ALCOHOLS DON’T HAVE ANY ALPHA–HYDROGENS SO NO RXN OCCURS

There needs to be at least one alpha-hydrogen to ‘lose’ such that a double bond with the oxygen can
form.
Oxidation of alcohols – Summary
Protection of Alcohols

Organolithiums (ex. Li(+) (–):C≡C–H) will act as a base before it will act as a
nucleophile, so any exposed OH group will have their proton stripped off by the
(–)
:C≡C–H.

Thus, if we want this organolithium to act as a nucleophile instead of as a base,

we need to protect the OH group first. Protecting groups can temporarily protect -
OH group from reacting and can then be removed later.

Protecting group example:

Preparation of mesylates and tosylates

The hydroxyl groups of alcohols are fairly poor leaving groups for nucleophilic substitution
reactions.

However, they can be reacted to form much better leaving groups called mesylates (Ms)
and tosylates (Ts).
• A mesylate is a compound containing the functional group –SO3CH3, derived from
methanesulfonic acid.
• Tosylates contain the functional group –SO3C6H4CH3, derived from toluenesulfonic
acid.
• These compounds are produced by reaction of alcohols with p-toluenesulfonyl
chloride or methanesulfonyl chloride.
• Mesyl and tosyl groups can also serve as protecting groups when we do not want
alcohols to react.
Mesylate and tosylate summary:
SN1 and SN2 – mini review

Recap on SN1 and SN2 reactions:

SN1 proceeds stepwise (leaving group first leaves, Nu attacks C +)

SN2 reactions occur in one step with a carbon transition state
SN1 reactions depend on the stability of the cation formed when the leaving group had left.
• Since tertiary carbocations are most stable of the three, tertiary carbons will undergo
SN1 reaction easily.

Order: Tertiary > Secondary >> Primary

SN2 reactions depend on the fastness of the leaving group.

• If the leaving group is more stable as an ion, then it'll leave faster.
• Also, the more bulky the substituents that are attached to the electrophile, the harder it
is for the nucleophile to attack the electrophile due to steric hindrance (ex. tertiary
carbons with three bulky groups)

Order: Primary > Secondary >> Tertiary

SN1 and SN2 reactions of alcohols

SN1 and SN2 mechanisms require: nucleophile, electrophile, leaving group

Example 1 (1° alcohol so SN2 reaction)

Since OH is not a good leaving group, we want to protonate it first to make it a much better
leaving group:

Now that we have a better leaving group, we can think about the SN2 reaction

Since the electrophile is not chiral, there will only be one product
Example 2 (2° alcohol so again, an SN2 reaction):

This time, TsCl / pyr is used to produce a better leaving group

Since the original OH group had stereochemistry, we have to consider that. The Nu attacks from
the opposite side, meaning that the final product will have the opposite confirguation

Example 3 (3° alcohol this time, so reaction will be SN1 instead)

No chiral center in the carbocation, so there is no stereochemistry to worry about in this

example

Formation of a better leaving group first:

SN1 reaction now proceeds

Aromatic Stability of benzene

Benzene is more stable than cyclohexene because it is aromatic

To be aromatic, a compound must satisfy two rules:

• Has 4n+2 (Huckel’s Rule) pi electrons in the ring
o n is any positive, whole integer
• Contains a ring of continuously overlapping ‘p’ orbitals (planar)

2 pi electrons/pi bond
1 pi bond/double bond
3 double bonds

= 6 pi electrons

6 = 4n+2 results in n=1, so part 1 of the rule is satisfied

Every carbon is sp2 hybridized, meaning that every carbon has a free p-orbital.
• Part 2 of the rule is satisfied
Aromatic heterocycles

Heterocycle – a cyclic compound that contains a hetero-atom in the ring (i.e. any atoms other
than carbon)
• Heterocycles can be aromatic too
o Ex. Pyridine

o Ex. Pyrimidine

Since the lone pair of electrons on the nitrogen occupies an sp2 hybridized orbital, it will not
participate in resonance
Pyrimidine in a biochemical context:

Although at first it is not obvious that thymine is an pyrimidine (or even an aromatic
heterocycle), we can see that it is if we look at its resonance structures:
Carboxylic acids

Carboxylic acid nomenclature and properties

(May use CA or COOH as short for carboxylic acids in this section)

Carboxylic acids have a carboxyl (COOH) group named after the carbonyl group (C=O)
and hydroxyl group.

Replace the -e ending of the alkane and add the ending ‘-oic acid’
Benzoic acid – CA attached to a benzene ring

Benzoic acid

Naming starts with 1 on the benzene ring at the attachment site for the CA functional group

If attached to a cyclohexane ring:

If two CA are present in one molecule, the ending becomes -dioic acid instead
Physical properties of CAs:

High BP (even higher that alcohols) since there are two ways for H-bonding to occur between
two Cas

Boiling points of carboxylic acids increases as the molecules get bigger

ex. BPheptanoic acid > BPheptanoic acid

Due to their polarity, Cas are soluble in water provided that the number of carbons in the R
group don’t give the molecule too much non-polar character (R with 5 or 6 carbons starts
becoming non-soluble in water)
Reduction of carboxylic acids (preparation of alcohols via LiAlH4 or BH3)
LiAH4 will reduce both ketones and CAs to alcohols

BH3 is selective for the CA, so even a ketone and a CA are both present, only the CA will get
reduced to an alcohol and the ketone will remain intact

Example:

Reduction of carboxylic acids – summary:

Preparation of esters via Fischer esterification

Removing water as it forms or increasing concentration of the alcohol will shift eq. to the right
and therefore drives the reaction.

Mechanism:
1) Carbonyl oxygen on the CA gets protonated.
2) Carbonyl carbon is now electrophilic (think resonance structure), and so the alcohol acts
as a Nu: and attacks it
3) Some B: (ex. alcohol) strips a proton off to help alleviate the positive charge.
4) One of the OH groups gets protonated by some source of protons (ex. protonated
version of alcohol), forming a nice leaving group
5) Leaving group leaves (as water) and the oxygen stabilizes the carbocation
6) Alcohol again acts as a B: to deprotonate
7) Final product is an ester.
Example 1:

Note how the oxygen in the final ester comes from the alcohol rather than from the OH of the
CA.

Example 2 (intramolecular):

The alcohol source is at the other end of the molecule to the CA group
If it helps, you can redraw the molecule as an open ring before you start.

Summary
• Fischer esterification: CA –––ROH + H+––> Ester + H2O
Preparation of acyl (acid) chlorides

Acyl chloride (aka acid chloride)

Example of a CA derivative

SOCl2 is very electrophilic

• You can either think of it in terms of resonance structures or δ+ due to the very EN oxygen and chlorine

Mechanism:
 1) Electrons from the oxygen of the OH move in to form a C=O such that the electrons in the original
carbonyl double bond can attack the electrophilic sulfur (which causes the electrons in the S=O to move
onto the oxygen)
2) Chloride anion is a great leaving group because it is stable on its own, so it leaves such that the oxygen’s
negative charge can be alleviated
3) (a) Chloride anion could function as a B: to alleviate the positive charge on the oxygen and form HCl
(b) Chloride anion could function as a Nu: and attack the electrophilic carbon
4) O(S=O)Cl is now a good leaving group (because some electrons can rearrange and it can form a gas plus
chloride anion), so it happily leaves, allowing oxygen to form a double bond with carbon
5) Deprotonation by some base (perhaps the chloride anion formed in step 4)
6) Acyl chloride + HCl

There are two other ways to make an acyl chloride too (shown in summary below):

Preparation of acyl (acid) chlorides – Summary:

Doesn’t have to be chlorine – could be bromine, etc.

Preparation of acid anhydrides

Terminology note:

Reaction conditions:

Mechanism:

R groups can be the same, or they can be different (making this a useful way to produce a
mixed acid anhydride)
Example 1:

Same source molecule used to produce the two reactants, and therefore the R groups on the
resulting acid anhydride are the same

Alternative mechanism – adding two specific CAs together under conditions of heat will lead to
a dehydration reaction that will also form an acid anhydride

NOTE: doesn’t work for most CAs, only really for the following two situations:
Preparation of amides using DCC

Terminology note:

R-COOH –––NH3 –––> R-COO– + NH4+

• Ammonia functions as a B: and takes a proton from the CA to become ammonium

So how do we produce an amide from a CA?

The presence of DCC allows your amine to function as Nu: instead of a B:, and therefore you
can get your desired product

Mechanism
1) DCC pulls a proton off of the CA’s OH group, making it O–
2) The electrophilic nature of the central carbon in DCC attacks the attention of the
nucleophilic O–, setting up a nucleophilic attack
3) Amine can now function as a Nu: and attack the electrophilic carbonyl C
4) DCC-O is now a good leaving group, allowing the carbonyl to reform
5) Deprotonation of the nitrogen group to neutralize the positive charge and complete the
reaction
6) Amide product formed from CA + Amine
Example 1: peptide bond formed between the N and C ends of two AAs:

Example 2: Amide in a ring = Lactam

DCC used to form an amide in a ring (lactam). In this example, the abx penicillin is formed and
has a beta-lactam ring. AbxR can form if a microbe encodes a beta-lactamase, which hydrolyzes
the beta-lactam ring and renders the abx ineffective.
Decarboxylation

Free rotation around the sigma bond allows for top structure to rotate into the bottom
structure

This allows for a bond to form between the carbonyl oxygen and the nearby hydrogen in a
cyclic mechanism that results in the production of CO2 (if heat is present)
This reaction is decarboxylation (loss of a carboxyl group as CO2)

Tidier graphic:

Requires there to be heat + a carbonyl beta to a COOH (i.e. two C away from the COOH group)

Example:
Alpha-substitution of carboxylic acids

Alpha-substitution of CA – substitution of an α-proton with some other substituent

• “Hell-Volhard-Zelinksy (HVZ)” reaction

Mechanism:
1) Standard preparation of an acyl bromide from a CA using PBr3
2) Acid-catalyzed keto-enol tautomerization to move from the keto form to the enol form.

Although Br-Br is usually non-polar (since the Br atoms are the same so have equal EN),
a dipole can be induced on this Br2 molecule such that there is some polarity. The pi
electrons of the alkene act as a nucleophile and attack the electrophilic Br (δ+). Loss of
the proton at the top too leads to the formation of HBr and our molecule in step 3
(alpha-bromo-acyl-bromide)

3) Now onto the second step of the reaction whereby we add H2O. The oxygen acts as a
nucleophile and nucleophilically attacks the electrophilic carbonyl carbon. Br anion is a
good leaving group. Water then gets deprotonated. (Loss of H+ and loss of Br– = loss of
HBr)
Example: AA synthesis by using a the HVZ reaction followed the addition of NH3
• Provided the NH3 acts as a nucleophile and not a base, we will have an SN2 reaction
whereby there is a substitution of the Br group with an amino group
CA reactions overview (article)

Since oxygen is more EN than carbon (and therefore pulls the electron density towards
itself) the carbonyl group (C=O) gets polarized (i.e. there is a charge separation), whereby
the carbon atom develops a partial positive charge (δ+) and the oxygen atom develops a
partial negative charge (δ-).

In general, carboxylic acids undergo a nucleophilic substitution reaction where the

nucleophile (-OH) is substituted by another nucleophile (Nu).

In some cases, in the vicinity of a strong electrophile, the partially negatively charged
carbonyl oxygen (δ-) can act as a nucleophile and attack the strong electrophile (as you will
notice in the example of acid chloride synthesis, see below).

Compounds in which the −OH group of the carboxylic acid is replaced by other functional
groups are called carboxylic acid derivatives, the most important of which are acyl halides,
acid anhydrides, esters, and amides.
Carboxylic Acid Derivatives – Overview

Common properties of CA derivatives:

• All have an acyl group (R-C=O) attached to a heteroatom
• Can all be synthesized from the “parent” CA
• All formed through a nucleophilic substitution reaction
• On hydrolysis (reaction with H2O), they all convert back to their parent CA

Acid chloride (R-O-Cl)

Acid chlorides are formed when carboxylic acids react with thionyl chloride (SOCl2), PCl3,
or PCl5.

They are the most reactive derivatives of carboxylic acid.

Mechanism of acid chloride formation with SOCl2

The electrophilic sulfur atom (think of it as δ+ because of the very EN oxygen and chlorine
groups) gets attacked by the nucleophilic oxygen of carboxylic acid to give an intermediate
six membered transition state

This transition state immediately decomposes to the intermediate (A) and HCl respectively.

This intermediate (A) then reacts with the HCl molecule, just produced, to give an
intermediate (B) which then collapses to form the corresponding acyl chloride, sulfur
dioxide and hydrogen chloride. This final step is irreversible because the byproducts,
SO2 and HCl, are gases that evaporate off and thus push the reaction in the forward
direction.
Ester (R-(C=O)-O-R’)
Esters are derived when a carboxylic acid reacts with an alcohol. Esters containing long
alkyl chains (R) are main constituents of animal and vegetable fats and oils. Many esters
containing small alkyl chains are fruity in smell, and are commonly used in fragrances.

The linking oxygen of the ester comes from the alcohol, not the OH group of the CA.

This occurs via Fischer esterification:

Thioester (RCOSR’)

Thio = sulfur

A thioester is formed when a carboxylic acid reacts with a thiol (RSH) in the presence of an
acid

Thioesters are commonly found in biochemistry, the best-known example being acetyl CoA.

The mechanism of thioesterification is the essentially the same as esterification. The only
difference being that instead of an alcohol (R’OH), a thioalcohol (R’SH) is involved

Acid anhydride (R-(C=O)-O-(C=O)-R)

As you can see, an acid anhydride is a compound that has two acyl groups (R-C=O) bonded
to the same oxygen atom. Anhydrides are commonly formed when a carboxylic acid reacts
with an acid chloride in the presence of a base.
Similar to the Fischer esterification, this reaction follows an addition-elimination
mechanism in which the chloride anion Cl- is the leaving group. In the first step, the base
abstracts a proton H+ from the carboxylic acid to form the corresponding carboxylate anion
(1). The carboxylate anion's negatively charged oxygen attacks the considerably
electrophilic acyl chloride's carbonyl carbon. As a result, a tetrahedral intermediate (2) is
formed. In the final step, chloride - a good leaving group - is eliminated from the
tetrahedral intermediate to yield the acid anhydride.

Amide (R-(C=O)-NR2)
The direct conversion of a carboxylic acid to an amide is difficult because amines are very
basic and tend to act as bases and convert carboxylic acids to their highly unreactive
carboxylate ions. Thus, DCC (Dicyclohexylcarbodiimide) is used to drive this reaction.
A carboxylic acid first adds to the DCC molecule to form a good leaving group, which can
then be displaced by an amine during nucleophilic substitution to form the corresponding
amide. The reaction steps are shown below:

Step 1: Deprotonation of the acid.

Step 2: Nucleophilic attack by the carboxylate.

Step 3: Nucleophilic attack by the amine.

Step 4: Proton transfer.

Step 5: Dicyclohexylurea acts as the leaving group to form the amide product.
Carboxylic acid derivatives

Nomenclature and properties of acyl (acid) halides

Start by naming the CA that the acyl halide came from, drop the -oic acid from the IUPAC name
(or just the -ic acid ending if the given name is the common name, such as acetic acid) and
instead add -yl (halide)

Physical properties:

BP:
• Molecules are polar and thus there is a dipole-dipole intermolecular force, which are
stronger than London Dispersion forces (ex. between two alkanes) but not quite as
strong as H-bonding (ex. between two CAs), thus the BP of acyl chlorides is somewhere
between the two.

Solubility:
• Although at a glance, the properties would make it look like it was soluble in water.
However, we can’t really say that it is, because it reacts so violently with water.

Summary:
• Acyl halide has a BP between that of alkanes and that of CAs
• Acyl halides react too violently with water to be considered soluble as such
 Nomenclature and properties of acid anhydrides

Start by naming the CA that the acid anhydride came from, drop the ‘acid’ from the name and
replace it with ‘anhydride’

Example 1:

Example 2:

Example 3 – derived from two different CAs

• Drop the acids, list alphabetically, and add ‘anhydride’
Physical properties

BP:
• Even more polar than the acyl halides, so good dipole-dipole interactions on top of the
baseline London Dispersion forces. Again, no H-bonding though, so not as high BP as
CAs, but dipole-dipole so higher than alkanes.

Solubility:
• Again, fairly reactive with water so hard to talk about the solubility as such.

Summary:
• Acid anhydrides have a BP between that of alkanes and that of CAs, though higher than
that of acyl chlorides (since it is more polar)
• Acid anhydrides react with water, so can’t be considered soluble as such

Nomenclature and properties of esters

Start by naming the R’ group

Then think about the CA that the ester came from, drop the -ic acid and instead add -ate
Example 2:

Example 3:

Example 4

Physical properties:

BP:
• London Dispersion + Dipole-Dipole interactions (but no H-bonding), so BP is between
that of alkanes (left) and alcohols (right) or CAs of similar sizes
Solubility:
• Polarity allows it to be soluble in water (to an extent, since the more carbons you add on
the chain, the more non-polar character the molecule gains)

Nomenclature and properties of amides

For 1° amides (N attached to 1 C):

• Start by naming the CA that the amide came from, drop the -oic acid from the IUPAC
name (or just the -ic acid ending if the given name is the common name, such as acetic
acid) and instead add -amide

For 2° amides (N attached to 2 C)

• Follow the same steps but at the beginning of the name add the N-R (where R is the
name of your substituent group)
For 3° amides (N attached to 3 C)
• Follow the same steps as for 1° but at the beginning of the name add the N,N-R’R’’
(where R is the name of your substituent group)

For amides where there is some other R group that you need to list:
• List like before but use the carbon number

Physical properties

BP:
 • Lots of opportunity for intermolecular H-bonding, making its BP (= 221°C) and MP (=
82°C) very high
o MP of 82°C means it is solid at room temperature

Solubility
• Amide a polar so dissolve in water (unless R group gets too make carbons)

Reactivity of CA derivatives

The reactivity of the CA-derivatives towards nucleophilic substitution is governed by the

nature of the substituent Y present in the acid derivative

If the substituent (Y) is electron withdrawing, then it increases the electrophilic nature of
carbonyl group by pulling the electron density of the carbonyl bond towards itself, making
the carbonyl carbon more reactive to nucleophilic substitution (inductive effect)
• Induction – electron withdrawing effect whereby electron density is withdrawn
from the carbon (both by the oxygen and by the EN substituent Y), which gives
carbon a δ+ and thus making it electrophilic, welcoming to a Nu: attack and
therefore making the CA-derivative more reactive

If the substituent (Y) is electron donating, it reduces the electrophilic nature of the
carbonyl group by neutralizing the partial positive charge developed on the carbonyl
carbon, and thus makes the derivative less reactive to nucleophilic substitution
• Resonance – competing effect whereby electron density is donated to the carbon
such that resonance structures can be formed (resonance = carbon’s δ+ is
neutralized = less electrophilic = less subject to a Nu: attack)
 o Alternative way to think of it: resonance = more stable = less reactive

Whether induction or resonance ‘wins’ determines the reactivity of the CA-derivative

Carbon is slightly more EN than Sulfur, making the thioester group (-SR) weakly electron
donating.

When is nitrogen electron donating and when is nitrogen electron withdrawing?

• When the N can participate in conjugation by resonance, it is strongly electron donating
since it can donate its free pair of electrons resonance (as in the example of an amide,
our CA derivative)
• When the N cannot participate in conjugation by resonance, it is electron withdrawing
due to the higher electronegativity of nitrogen atom compared to carbon atom.
Note: the video says the induction is still stronger for esters (though not as strong as it is for
acid anhydrides and acyl halides). Either way, the order stays the same:

Nucleophilic acyl substitution

Factors that influence the chance of a Nu: acyl substitution reaction:

• Strength of the electrophile
o i.e. reactivity of the CA-derivative (last lecture)
 • Strength of the nucleophile
• Stability of the leaving group
• Steric hindrance
o Bulky R group = steric hindrance = less chance that Nu: can attack

Stability of the leaving group:

• When you form the tetrahedral intermediate, there are theoretically three different
groups that could be the leaving group

• How do you know which is the ‘best’ leaving group?

o Think about the conjugate acid of the leaving group and their pKa values (even if
you don’t know the exact pKa values, you can at least order lowest pKa/most
acidic to highest pKa/least acidic)
o The most acidic compound is the compound that is most willing to donate a
proton (and therefore exist in the deprotonated form), because it is the most
stable in its anion form.

o By thinking about it this way, we now know that the chloride anion is the most
stable out of these three possible leaving groups, and therefore it is the group
that will leave the tetrahedral intermediate in our mechanism
 Acid-catalyzed ester hydrolysis

Recall: Fischer esterification

Increasing the concentration of H2O will shift eq. to the left and will drive the reverse reaction:
ester hydrolysis

Mechanism:
Example 1

Example 2
Transesterification:
• Similar reaction, but instead of using H-OH (water), we are now using R-OH (another alcohol).

The reaction can be forced either way by adding or removing reagents or products (since the reaction
will move back to equilibrium)

Acid and base-catalyzed hydrolysis of amides

Amides are pretty unreactive due to resonance stabilization.

However, you can get them to hydrolyze if you use harsh reaction conditions (such as strong
acid with heat, or a strong base)

Strong acid + heat

Mechanism:
Strong base

Mechanism:

Examples:
 Beta-lactam antibiotics

Lactams are a type of amide (lactam = amide in a ring), but are not quite like typical amides:
• Typical amide:
o Nitrogen’s lone pair of electrons is not localized to the nitrogen (i.e. can shift into
a C=N bond during resonance)

• β–Lactam:

o The fused 4-5-ring system prevents the nitrogen from being planar.
o Since it’s not planar, you don’t get the same kind of resonance stabilization that
we had in the typical amide
▪ Thus, the nitrogen can’t donate as much electron density to the carbonyl
carbon, making the carbonyl carbon inherently more reactive (more
electrophilic)
▪ Think of it like: loss of resonance stabilization = less stable = more reactive
▪ This is the first reason why β-lactams are easily hydrolyzed.

The second reason why β-lactams are easily hydrolyzed is because of ring strain:
 • See how the sp3 hybridized carbon (ideal bond angle of 109.5°) looks to be at an angle
closer to 90° when in the 4-membered ring.
• The more you deviate from the ideal bond angle, the more ring strain (angle strain)
there is.
• The best way to alleviate this ring strain is to break the bond (hydrolyze the ring) and
open it, allowing the bond angle to move closer to the ideal bond angle of 109.5°

Summary: ring strain and lack of resonance stabilization make the β-lactam ring (the ring form
of an amide) inherently very reactive.

Mechanism of action of penicillin:

• Transpeptidase enzyme is an enzyme used by bacteria to build their CW
o It is classified as a type of Penicillin Binding Protein
• The enzyme has an OH group
• The enzyme’s OH group acts as a Nu: to attack the highly reactive carbonyl carbon of
the beta-lactam ring, hydrolyzing the amide and resulting in the enzyme becoming
sequestered and disabled (loss of its active OH group)
• Bacteria can no longer build its CW
Enzymes

Introduction to enzymes and catalysts

Catalysts = makes a reaction go faster

Enzyme = biological catalyst
• Thus, enzymes increase the rate of biochemical reactions

Catalysts make reactions go faster by using one of four catalytic strategies:

1) Acid/base catalysis
• Enzyme acts as either an acid or a base, which are good proton carriers.
• Ex. keto-enol tautomerization reaction requires the movement of a proton. Since
acids and bases are both good proton carriers, they can catalyze the reaction

2) Covalent catalysis
• Enzyme forms a covalent bond with another molecule (typically their target
molecule)
o Recall: a covalent bond involves to molecules sharing electrons
o Enzymes that are electron carriers (or electron ‘sinks’) can thus catalyze
these types of reactions
3) Electrostatic catalysis
• Enzyme can provide charge stabilization (by having a metal cation)
• Example: DNApol uses the metal cation Mg2+ to stabilize the negative charge of the
DNA backbone

4) Proximity & Orientation effects

• Enzyme brings molecules together and orients them correctly such that there is an
increase in the frequency of successful collisions

SUMMARY:
 Induced fit model of enzyme catalysis

Catalyzed reactions have a much smaller activation energy (AE) than uncatalyzed reactions.
• As a result, the reaction’s transition state energy is lower too

Active site – site on the enzyme where substrates bind, where the reaction ultimately happens
• Unique for each enzyme and specific to specific substrates

Induced fit model

• Initial binding is like ‘docking’, whereby the substrate and enzyme are
interacting/binding strongly but not at full strength.
• Induced fit follows, whereby the enzyme and substrate have changed their shape a
little to bind each other tightly. Binding forces are at full strength.
o This is the transition state
[E-X]‡ is the transition state
• Substrate is represented as ‘X’ since it isn’t quite a product but is no longer a substrate,
• ‡ just represents transition state
• Binding is strongest during the transition state, because this is when the enzyme and
substrate have molded together

Some enzymes can bind more than one substrate

Allosteric site – any site outside of the active site

Allosteric binding – molecule binds at a different location than the enzyme’s active site, often
causing a conformational shape change in the active site of the enzyme and thus affecting its
ability to bind to substrate
• Ex. an inhibitor
Six types of enzymes
 An introduction to enzyme kinetics

Rate at which a reaction proceeds is dependent on the constant ‘k’ and the concentration of
the enzyme and substrate

Rate is equal to the rate of change of the concentration of our product with respect to time

If we assume that k is constant, then the only way to increase the rate is to increase either [E]
or [S]
Generally in the cell, total [E] is constant
• Ex: 4 enzymes, each of which can catalyze 10 reactions per second
• Vmax is the maximum rate, the total number of reactions that can be catalyzed per
second by the cumulative effort of the enzymes
o When Vmax is reached, even increasing [S] won’t increase the number of
reactions catalyzed per second, since the enzymes are working at full capacity
 Allosteric regulation and feedback loops

Michaelis-Menten equation:

• V0 = initial velocity of the reaction

• Vmax = maximum rate of the reaction
• [S] = concentration of substrate
• Km = Michaelis-Menton constant

Allosteric regulators bind to allosteric sites (which exist anywhere on the enzyme) to regulate
the activity of the enzyme
• Allosteric activators increase enzymatic activity
o Either by increasing Vmax or decreasing Km
• Allosteric inhibitors decrease enzymatic activity
o Either by decreasing Vmax or increasing Km
Feedback loop – downstream products regulate reactions upstream
• Positive feedback loop – a change that causes an even further change in the same
direction
• Negative feedback loop – a change that causes a change in the opposite direction

Example:

Consider this step in glycolysis

Glycolysis is the process by which cells use to make ATP. Thus, ATP is a product of the pathway.
ATP is also an allosteric inhibitor of phosphofructokinase as part of a negative feedback loop to
ensure that glycolysis is downregulated when ATP levels are adequate.
• However, this is an interesting case, because while ATP is the product that feeds back to
inhibit the enzyme, it is also a substrate for the enzyme (see in the pathway above how
it is a substrate too)
o Homotropic regulator – a molecule that is both a substrate and a regulator

AMP is an allosteric activator of phosphofructokinase that turns on glycolysis when ATP levels
are low.
• AMP is a regulator but not a substrate for the enzyme
o Heterotrophic regulator

This reaction in particular has a ΔG° = –4.5 kcal/mol, meaning that a lot of energy is released
from the reaction. This makes the reaction more or less a one way reaction, making it an
excellent control point for all 10 steps of glycolysis
Kinetics

Simple example:

More complicated example:

Rate is referring to reaction rate, and in the above reaction, reaction rate = rate of oxygen
formation simply due to the fact that oxygen has a molar coefficient of 1 by chance. You can
find rate from any of the others too so long as you divide by the right coefficient (which is
shown in green and cyan)

Rate law and reaction order

Lowercase letters = coefficients for the balanced equation

Uppercase letters = reactants

Increasing the concentration of either of the reactants increases the rate of the reaction (for
most reactions)

Initial rate – rate before any products have formed (rate starts to slow as products form since
the reaction is reversible)

Rate law
• First, we need to derive the exponents using the given concentrations and initial rates,
like so:

o Found that the reaction is first order in A, and second order in B

 • Then we can write our rate law:

These orders have to be determined experimentally.

• They are NOT just equal to the equation coefficients!

The overall order will affect the units for the rate constant (k)

These units are only true for this specific example, but will change if overall order changes

Another example:

See how now we have an overall order = 0, and the units for k have changed.
 Experimental determination of rate law

When [NO] increased by a factor of 2, Initial Rate increased by a factor of 4. Since 4 = 2x, x = 2
• Reaction is second order for NO
When [H2] increased by a factor of 2, Initial Rate increased by a factor of 2. Since 2 = 2y, y = 1
• Reaction is first order for H2
•

Overall order = 1 + 2 = 3

Rate constant (k) for the given temperature can be found by plugging in any one set of numbers
into our rate law:
We can now use our rate law (with our value for k) to solve problems:

Summary of zero, first-, and second-order reactions

(including rate, integrated rate law, and graph)
 Plotting data for a first-order reaction

Plotting the data under using the first order integrated rate law gave us a straight line, which
proves that this is a first-order reaction.

The rate constant (k) was then determined by finding the slop of the line, and since the
integrated rate law tells us that the slope = -k for first order reactions, we take the negative of
the slope to find rate constant k.
First-order reaction example
Plotting data for a second-order reaction
Second-order reaction example
 Collision Theory

Activation energy (Ea) – the minimum amount of energy that is required to initiate a chemical
reaction

Transition state (aka activated complex) – old bond breaks as the new bond forms.

ΔE = Ep – Er
• Change in energy (ΔE)
o If negative, reaction is exothermic (meaning that heat is given off)
▪ Products are at a lower energy than the reactants, so this energy has to
‘go’ somewhere
o If positive, reaction is endothermic (meaning that heat is absorbed)
▪ Products are at a higher energy than the reactants, so this energy has to
‘come from’ somewhere
• Energy of the products (Ep)
• Energy of the reactants (Er)
Exothermic reaction – example:

Endothermic reaction – example

 Arrhenius equation + Forms of the Arrhenius equation

–> Standard form:

–> Form that is useful for graphing:

–> Form that can be used when you don’t have A (frequency factor) but do have the rate
constants (k1 and k2) at two different temperatures (T1 and T2):

Using the Arrhenius equation

If asked to find activation energy (Ea), there are two approaches:

1) Graph the data points using the y = mx+b form of the equation, then find the slope. Slope =
m = -Ea / R, so you would just multiply the slope by -R to get Ea

2) Use the equation that just needs the rate constants (k) at two different temperatures (T)
 Elementary rate laws

Elementary reaction – a one-step reaction whereby one or more molecules react directly to
form products in a single reaction step with a single transition state.
• For elementary reactions only, the coefficient in the balanced chemical equation
actually can be used to write the rate law.
 Mechanisms and the rate-determining step

Mechanism – the sequence of elementary steps by which a reaction proceeds

Elementary steps must add up to the overall reaction

Intermediate – a molecule that is produced in one step but used in a later step, and is therefore
neither a reactant nor a product (i.e. is not present in the final equation)
• ex. NO3 in our example
• Detecting intermediates during a reaction can be useful to help chemists determine
mechanisms
Possible mechanism must be consistent with the experimental rate law

Rate-determining step (RDS) – the slowest elementary step in the mechanism

• Rreaction ≈ RRDS
o Overall reaction rate ≈ the rate of the RDS

o Thus, if we can determine RRDS, then this is a good approximation of Rreaction.

▪ Since the RDS alone is an elementary step, we can use the tools learned
in the last lecture to write the rate law using the coefficients.

▪ If this matches the experimental rate law for the reaction, then we can
say that the possible mechanism is consistent with the experimental
rate law
 Catalysts

Catalyst – a substance that increases the rate of the reaction without being consumed in the
reaction.

Example with I– as a catalyst:

Elementary steps must add up to the overall reaction

Catalysts are present at the first and last step of the mechanism, so cancel out of the final
equation.

Possible mechanism must be consistent with the experimental rate law

Use elementary step 1, since it is the RDS.

Catalysts lower the Ea by offering an alternative mechanism.
• The Arrhenius equation tells us that decreasing Ea will increase k (which in turn
increases R), explaining why catalysts will speed up a reaction
 Kinetic and thermodynamic enolates (replicate):

Kinetic enolate:

LDA is a strong base but is bulky, and will therefore ‘approach’ the reactant (aldehyde or
ketone) from the least sterically hindered side (if performed under cold temperature rx
conditions)

In this case the least sterically-hindered side is the RHS with the methyl group, since the LHS has
a methyl group + an R-group. Thus, LDA will pull off an α-proton from the RHS.

The product in this case is the kinetic enolate, meaning that it is the product that forms fastest
• It forms the fastest due to
o (a) the use of a sterically hindered base at low temperatures (e.g. LDA at –78 °c)
o (b) probability, since there are 3 α-protons to choose from on the RHS Cα but
only 2 α-protons to choose from on the LHS Cα

Thermodynamic enolate:

Hydride anion (H–) is used as a base instead:

The product in this case is the thermodynamic enolate, meaning that it is the product that is
most stable (see below)
Comparing the stability of the kinetic vs. thermodynamic enolate ions:

The more substituted the double bond of a C=C bond, the more stable the bond (a substituent
is any atom or group of atoms that replaces a hydrogen atom).
• In the case above, the double bond of the thermodynamic enolate is more substituted
(R, O, and C) than the double bond of the kinetic enolate (C-R, O)
• Thus, although the kinetic enolate forms faster, the thermodynamic enolate is more
stable.

You can control whether the kinetic or thermodynamic enolate ion forms depending on
which base you use (LDA vs. H–) and reaction conditions (cold temperature)
Equilibrium

Reactions in equilibrium

Equilibrium – a state in which the forward and reverse rates of a reaction are equal
• Doesn’t mean that the concentrations on either side of the equation are equal
• Can occur when products and reactants have similar energy states

Le Chatelier’s principle

Le Chatelier’s principle – when you stress a reaction that’s in equilibrium, the reaction will
favor one side of the reaction to relieve that stress and re-reach equilibrium.
 Changes in free energy and the reaction quotient

Example 1 (standard conditions):

Pressure can be used in the reaction quotient formula if you are given pressure rather than
concentration.

ΔG = ΔG° in this example, which is logical since the example is under standard conditions (25° C
and 1 atm)
Example 2 (non-standard conditions):

If we compare Q to K (experimental value for the equilibrium constant), we find that Q <<< K.

Since K has the reaction lying far to the right, but Q says the reaction is currently lying far to the
left, we know that there will be a strong, spontaneous driving force in the rightward direction
to reach equilibrium.

As the reaction progresses, Q will approach and eventually equal K.

• As this happens, As Q increases, ΔG approaches and eventually equals 0.
• Thus, there is no more driving force for the reaction to occur
 Standard change in free energy and the equilibrium constant

By plugging in ΔG = 0 (which is true at equilibrium) into the formula, we can

come up with another formula:

Example 1:
Example 2:

Example 3:
Summary

Galvanic cells and changes in free energy

Didn’t feel like notes needed making.

Bioenergetics

Bioenergetics: The transformation of free energy in living systems

How does energy from the sun -> energy for our body to use?

1) In the light reaction (occurring in the chloroplasts of plant cells). the energy in energy in
sunlight causes H2O to ‘kick off’ a hydrogen ion, which then gets bound to NADP to form
NADPH, forming a small amount of ATP. However, NADPH is a high-energy e– carrier that can
be used to produce a lot more energy in the next step.

2) In the Calvin cycle, CO2, and NADPH + ATP from the previous step undergo a series of
reactions that results in glucose formation. ‘

3) Animal eats the plant and gets its glucose. Glucose first gets broken down into pyruvate,
yielding a small amount of ATP.

4) Pyruvate -> Acetyl-CoA, which then enters the TCA cycle which results in a series of reactions
that results in the production of CO2, NADH, and FADH2.

5) These high energy electron carriers (NADH and FADH2) now enter the ETC, whereby H+ is
bumped off a number of different steps and used to drive the ATPase (creating ATP). These
hydrogens eventually combine with O2 to form H2O
Photosynthesis and cellular respiration and very similar reactions but in reverse directions

Photosynthesis Cellular respiration

Why do we need metabolism?

Metabolism – the flow of energy throughout the body

• Functions to convert energy from various sources (ex. different macronutrients) into a
common and utilizable form of energy that our cells can use
Insulin and glucagon
 Tissue specific metabolism and the metabolic states

Absorptive state
• A series of metabolic reactions that occur when food is in plenty. Food is in the
intestines and being absorbed, and it wants to be stored of later use.
• Generally anabolic
• LIVER
o Glucose -> One of two paths:
▪ 1) Glycogenesis (Glucose -> Glycogen)
▪ 2) Glucose -> Glycerol + FAs -> TAG -> VLDL (for transport via blood to
adipose)
• Note:
o Glucose -> Pyruvate -> Acetyl-CoA -> Palmitate (the only
FA we can self-synthesize)
o AAs -> α-keto acids + NH3
▪ NH3 -> urea -> excreted as waste
▪ α-keto acids -> One of two paths:
• 1) α-keto acids -> FAs (and then follows the above pathway)
• 2) α-keto acids -> Acetyl-CoA -> TCA -> ETC -> ATP
• ADIPOSE
o Glucose -> Glycerol + FAs -> TAGs
o VLDL -> FAs
▪ FAs + Glycerol -> TAGs
• MUSCLE
o Glucose -> One of two paths:
▪ 1) Glycogenesis (Glucose -> Glycogen)
▪ 2) Glycose -> Pyruvate -> Acetyl-CoA -> ATP
o AAs -> Protein
• BRAIN
o While most of the body is storing energy, the brain doesn’t store any, it just uses
it
o Glucose -> Pyruvate -> Acetyl-CoA -> ATP

Zoom:
Post-absorptive state
• Break-down and release of stored energy
• Generally catabolic
• LIVER
o Glycogen -> Glucose -> Blood -> Utilized by cells around the body
o AAs -> α-keto acids + NH3
▪ NH3 -> urea -> excreted as waste
▪ α-keto acids -> One of two paths:
• 1) α-keto acids -> Glucose
• 2) α-keto acids -> Acetyl-CoA -> TCA -> ETC -> ATP
o FAs and glycerol -> Glucose
o FAs -> Ketones (usable by the brain)
• ADIPOSE
o TAGs -> Glycerol + FAs -> Blood -> Liver -> Glucose
• MUSCLE
o Protein -> AAs -> Blood -> Liver -> α-keto acids -> Glucose
o (Aerobic) Glycogen -> Glucose -> Pyruvate -> Acetyl-CoA -> ATP
o (Anaerobic) Glycogen -> Lactate + ATP
• BRAIN
o Glucose -> Pyruvate -> Acetyl-CoA -> ATP
o Ketones -> ATP

Zoom:
Thermodynamics
Closed system – a system in which matter cannot be exchanged with the surroundings, only
energy.

Thermodynamics (article)

0th Law of Thermodynamics – if two systems are in thermal equilibrium with a third system,
then they are in thermal equilibrium with each other
• Thermal equilibrium – systems are at the same temperature (i.e. two systems in contact
with each other have no energy flow taking place between them)
• If T1 = T3, and T2 = T3, then T1 = T3

1st Law of Thermodynamics – the change in internal energy of a closed system is equal to the
energy adding to it in the form of heat (Q) plus the work (W) done on the system by the
surroundings
• ΔEinternal = Q + W = Q + PΔV
o May see ΔEinternal denoted as ΔU
o Q = Heat
▪ Heat is energy transferred to the motion of atoms and molecules
o W = Work done on the gas
▪ Work is energy transferred to the motion of objects
o –Q Heat flows out of the system
o +Q Heat flows into the system
o –W Work is done by the system
o +W Work is done on the system
• Essentially just an application of the law of conservation of energy.
• Whenever heat energy is added to a system from outside, some of that energy stays in
the system, and the rest gets consumed in the form of work.
• Energy that stays in the system increases the internal energy (ΔU) of the system
o Internal energy involves all the translational, rotational, and vibrational kinetic
energy of a gas
Example 1:

U ∝ T, meaning that when internal energy goes down, so does temperature, and v.v. (logical)

Example 2:
Example 3:

May use with W = PΔV

• Work (W)
• Pressure (P)
• Change in volume (ΔV)
2nd Law of Thermodynamics – the total change in entropy (S) of a system plus its surroundings
will always increase for a spontaneous process
• Entropy is a measure of disorder in a system
• Every system ‘wants to’ achieve a state of maximum disorder
• Heat will never flow spontaneously from a colder object to a hotter object
o Ex: ice spontaneously melts when left at room temperature. Ice is a solid with an
ordered crystalline structure as compared to water, which is a liquid in which
molecules are more disordered and randomly distributed. This would never
occur spontaneously (but can be forced, ex. put it in the freezer).
• The way that systems go from ordered to disordered is just a statistical result from
counting up the possible number of states:
o Macrostates (1 of 2):
▪ 1) Molecules are ordered in terms of position, velocity, energy, etc.
▪ 2) Molecules are disordered in terms of position, velocity, energy, etc.
o Microstates:
▪ An exact description of how the molecules of a macrostate are
distrusted.
▪ Even though one particular ordered microstate is just as likely to occur as
one particular disordered microstate, there is a much higher probability
 that a system will be in a disordered state simply because there are so
many more disordered microstates as compared to ordered microstates
▪ Analogy: only a few ordered microstates for a deck of cards, but there are
many more disordered microstates.

o Entropy of the universe is constantly increasing (and is therefore always greater

than zero)
• Entropy (S) = Q/T (units: Joules per Kelvin)
• When a reaction is at equilibrium, ΔS = 0 (it has to be if ΔG is – see equation below)

Enthalpy (H) – the overall amount of energy in the system, while considering pressure and
volume too.
• ΔH comes about when there is a change in bond energy

Gibb’s free energy (G) – Predictor of spontaneity of a chemical reaction at constant

temperature and pressure
• Gibb’s free energy is the energy associated with a chemical reaction that can be used to
do work
3rd Law of Thermodynamics – the entropy of a perfect crystal of any pure substance
approaches zero as the temperature approaches absolute zero.
• Analogy – penguins form colonies or groups whereby they huddle in a tightly-packed,
unmoving fashion, all facing the same direction. Just like the penguins, atoms in a pure
crystalline substance get aligned perfectly and do not more around.
• Matter is in a maximum order (least entropy) when temperature approach absolute
zero (0 Kelvin).
• This means that any thermal motion ceases in a perfect crystal at 0 K.
 Specific heat and latent heat of fusion and vaporization

Specific heat

Specific heat (c)

• Specific to the material and the phase that said material is in
• Some materials require more heat to achieve the same increase in temperature
o Water has a high specific heat (c), making it a ‘heat sink’ – it can store a
lot of heat energy without raising in temperature that much
* Can’t use across phases *

Example: copper cube is dropped into water. What is the temperature of the system when it
reaches equilibrium?

Qc + Qw = 0, since the water gains the exact amount of heat that the copper loses.

Latent heat of fusion (liquid -> solid) and vaporization (liquid -> gas):
• The extra heat needed for in order to cause a change in phase (once you have already
got to the appropriate temperature)
Example: How much energy to boil the water in the image on the right

Q=mL = 2*2,260,000 J, then add that to the Q in red

Example 2:

PV diagrams (Pressure-Volume diagrams)

Four most common thermodynamic processes that are represented on PV diagrams:

1) Isobaric expansion or compression

• Iso = constant
• baric = pressure
Area under the curve is significant
• For isobaric processes, Area under curve = PΔV = Work
• Important to be really careful with the sign for W.
o Find area and then look at direction. If you’re going to the left, work is positive,
if you’re going to the right, work is negative. Can also deduce this by thinking
about it:
▪ Going to the right means that volume is increases which means that
work is being done by the system (gas), which makes W negative.
▪ Going to the left means that volume is decreasing, which means that
work is being done on the system (gas), which makes W positive.
2) Isothermal expansion or compression
• Iso = constant
• thermal = temperature
• ΔT = 0, and therefore ΔU = 0 (since ΔU ∝ ΔT)
o Since ΔU = 0 = Q + W, we know that Q and W must be the exact same
magnitude (but opposite signs)
o Δ(PV) = 0 too, since it is related to ΔT by the ideal gas law
3) Isometric/isochoric/isovolumetric
• Iso = constant
• volumetric = volume
• Since the volume is being kept constant, no work can be done (W = 0)
• This means that ΔU = Q
o The only way to change the internal energy is to add or remove heat
4) Adiabatic expansion or compression
• “no heat exchanged”
• Does not mean ΔT, it just means Q = 0 (no heat is allowed to flow in or out of the gas)
o The temperature can still change because work can be done by the piston
o Important distinction: Temperature ≠ Heat
▪ Temperature is a measure of the amount of energy that a gas has at a
given moment. Heat is how much thermal energy is flowing in or out of
a gas (which is 0 in an adiabatic process)
• ΔU = W

• Looks like isothermal, but is steeper

Summary:
Thermochemistry

Phase diagrams

Phase diagrams are used to show conditions (such as pressure and temperature) at which
thermodynamically distinct phases occur and coexist at equilibrium.

Critical point – the point on a phase diagram at which both the liquid and gas phases of a
substance have the same density, and are therefore indistinguishable
 Enthalpy

Internal energy change (ΔU) – the heat absorbed or evolved by a system when you assume a
constant VOLUME
• Q = ΔU + PΔV
• ΔV = 0, so
• Q = ΔU

Enthalpy change (ΔH) – the heat absorbed or evolved by a system when you assume constant
PRESSURE
• Q = ΔU + PΔV
• Q = (Uf-Ui) + P(Vf-Vi)
• Q = (Uf + PVf) – (Ui + PVi) Note: Enthalpy (H) H = U + PV
• Q = Hf – Hi
• Q = ΔH

Enthalpy is a state variable (a variable that is not dependent on the path by which the system
arrived in its present state). Enthalpy doesn’t ‘do’ anything, it is just a quantity in a system.

Enthalpy is similar to energy, but broader since it accounts for pressure and volume in addition
to all that energy accounts for.
 Endothermic vs. exothermic reactions

Endothermic – the system absorbs heat from the surroundings

• Ex. Photosynthesis (CO2 + H2O + heat ––> Glucose + O2)
• Ex. Cooking an egg (heat is absorbed by the egg (system) from the pan (surroundings))

Exothermic – the system releases heat into the surroundings

• Ex. Combustion (CH4 + O2 ––> CO2 + H2O + heat)
• Ex. Rain (water vapor condenses into rain, releasing energy in the form of heat)

Heat is released (exothermic) when chemical bonds are formed

Heat is absorbed (endothermic) when chemical bonds are broken

• Why? Molecules inherently want to stay together, so formation of chemical bonds

between molecules requires less energy as compared to breaking bonds between
molecules, which requires more energy and results in heat being absorbed from the
surroundings.
• A way to think about it – the energy in a covalent bond between two molecules is less
than the sum of the separate energies, so when you form a covalent bond, there is ‘left
over’ energy, which manifests as heat.

Enthalpy – defined as the heat energy change (ΔH) that takes place when reactants -> products
• Exothermic reactions have a negative ΔH
• Endothermic reactions have a positive ΔH
Example: Exothermic reaction (therefore ΔH is negative)
 Heat of formation, Hess’s law, and reaction enthalpy change

Hess’s law

Hf° means heat of formation at standard conditions (kJ/mol)

Δ Hf° = 0 when the element is in its standard state (most stable form) (ex. oxygen as O2, carbon
as C, hydrogen as N2, iron as Fe, etc.)

May also be given something like this:

* Skipped some videos in this section because they seemed convoluted. If this topic isn’t clear
when it comes to practice, check these notes but then try some other resources *