Chapter 2 1

CHAPTER 2
1. Explain each of the following trends.
(a) Since the phenyl ring is somewhat electron-withdrawing, the three phenoxide anions are less
basic than the cyclohexanol anion. The OMe group is electron releasing, and this makes the availability
of electron density on O– greater than on phenoxide. Similarly, the nitro group is electron withdrawing,
making the electron density on O– less than in phenoxide.
(b) When comparing formic acid and acetic acid, the electron releasing methyl group in acetic acid
diminishes the positive character of the acidic hydrogen. It is therefore less acidic. In addition, once
ionized to the carboxylate, the presence of the electron releasing methyl group slightly diminishes the
adjacent positive character of the carboxyl carbon, destabilizing the anion relative to the formate anion.
The smaller formate anion is probably better solvated than the acetate anion, which also contributes to
enhanced acidity.
ortho-Methoxyphenol is more acidic than para-methoxyphenol due to the "ortho effect." The
proximity of the OMe in the ortho derivative allows internal hydrogen bonding with the O—H moiety,
making that bond more polarized and more acidic. Such internal hydrogen bonding is not possible in the
para derivative, although intermolecular hydrogen bonding may occur.
Acetic acid is more acidic in water, although THF is a stronger base. Ionization is much easier in
water than in THF, and water can better stabilize the ionic products. This makes the ionization (loss of
H+) easier, enhancing acidity relative to THF where ionization is less efficient.

2. Offer a mechanistic explanation for the following transformation.

See Tetrahedron Lett. 2000, 41, 3411. The tertiary allylic alcohol reacts with the acidic resin (H+)
to give the oxonium ion. There are two pathways. An SN2' displacement of water by the primary alcohol
unit leads to the product directly. This is the mechanism presented by the authors of this paper. An
alternative mechanism would be ionization to an allylic tertiary cation followed by cyclization and loss of
a proton, as shown in the diagram.

HO H2O
+ H+ SN2'
OH OH
O
- H2O

- H2O

- H+

vinylogous
SN1-like OH H
O
Tetrahedron Lett. 2000, 41, 3411
2 Organic Synthesis Solutions Manual

3. The following reaction gives a mixture of the alcohol and the ether, in the proportions given later
in this question. Only 0.03 eq of oct-1-ene were used. In each case, a 1:1 ratio of water to alcohol
was used.
This reaction proceeds via a mercury-stabilized secondary cation. In this paper, a detergent
(sodium dodecyl sulfate) was added. The cation formed in the reaction can react with water (from the
aqueous solvent) to give an alcohol after reductive cleavage of the C—Hg bond with sodium borohydride.
The ether is formed by attack of octan-1-ol on the cation. There is a large excess of water, however, so
the alcohol is the major product. Increasing the proportion of octan-1-ol leads to increased amounts of
ether. Even when 10 equivalents of octan-1-ol are used, however, water is present in a large excess. In
fact, water and octan-1-ol are close in nucleophilic strength.
The presence of the detergent had an influence on the reaction. The detergent led to enhanced
local concentrations of octan-1-ol that can overcome the bulk concentration effects of the excess water,
leading to more ether product. Taken from J. Org. Chem. 1987, 52, 5039.

4. Two products are formed in the following reaction, A and B. (a) Offer a reasonable explanation
of how B could arise in this reaction. (b) Would the use of the 4-chlorophenyl derivative, rather
than the 4-methoxy derivative help or hurt formation of B? Why or why not?

This problem was taken from J. Org. Chem. 1987, 52, 260; 1984, 47, 4855.
(a) Product A is the usual product of reaction of an alkene with chlorine. Formation of
chloronium ion X was followed by addition of chloride ion to give A, as shown. Product B arises by a
cationic mechanism that involves participation of the aromatic ring. If chloronium ion X opens to form
cation Y, the benzene ring attacks the positive charge to form the bridged cation Z. If chloride ion attacks
the three-membered ring, as shown, B results.
MeO Cl
MeO MeO

Cl—Cl MeO Cl
Cl
Cl
Z
X Y
Cl
Cl
MeO

MeO

Cl Cl

A B
Cl

(b) If the OMe group, which is electron-releasing, is replaced with Cl, which is electron-
withdrawing, product B should be more difficult to form. While the electron releasing OMe group will
stabilize cation Z, an electron withdrawing Cl will destabilize this intermediate, making formation of Z
more difficult and, thereby making formation of B more facile.
 Chapter 2 3

5. Explain each of the following.

(a) The proximity of the ammonium group to the carboxyl carbon is the key to this answer. The
aminopropanoic acid has the amino group two carbons away, whereas the amino group is four carbons
away in aminopentanoic acid. Both inductive effects and field effects are strongest when the ammonium
groups are close. For this reason, aminopropanoic acid is more acidic than aminopentanoic acid.
(b) The nitro group in 4-nitrophenol is electron withdrawing and, therefore, stabilizes the charge
in the phenoxide product. No such stabilization is possible with phenol. The electronic effects also
weaken the O—H bond, enhancing acidity.

6. Offer a mechanistic explanation for the following transformation.

See Synthesis 1996, 219. Since NBS is a source of bromine, reaction with the alkene unit
generates a bromonium ion. The oxygen of the alcohol is fixed on the bottom of the molecule relative to
the Br, and properly positioned to open the bromonium ion to form the ether unit. This places the
bromine on the top of the molecule.

H NBS , CH2Cl2 H
Br
OH -25°C → RT
O
H
Br H
Br2 from NBS Br - H+

O
HO H

7. Calculate the pKa given the following values for Ka:

(a) Ka = 6.35x10–6 : pKa = 5.2 (b) Ka = 12.1x107 : pKa = -8.1
(c) Ka = 18.5x10–12 : pKa = 10.7 (d) Ka = 9.2x10–3 : pKa = 2.04 (e) Ka = 10.33x108 : pKa = –9.0
(f) 0.08x10-3 : Ka = 4.1

8. Calculate the Ka given the following values for pKa:

(a) pKa = 6.78 : Ka = 1.66 x 10–7 (b) pKa = -3.2 : Ka = 1584
(c) pKa = 23.5 : Ka = 3.12 x 10-24 (d) pKa = 10.3 : Ka = 5.01 x 10-11
(e) pKa = 35.8 : Ka = 1.583 x 10–36 (f) pKa = –11.1 : Ka = 1.26 x 1011
4 Organic Synthesis Solutions Manual

9. Draw complete reactions for (a) Propanoic acid (b) Methanesulfonic acid with (i) NaOH, and
then (ii) NaNH2, showing all starting materials and all products.
O HO- O

OH O- + H2O
(a) O O
H2N-

OH O- + NH3

(b) CH3SO3H CH3SO2- + H2O

CH3SO3H CH3SO2- + NH3

10. Careful analysis shows that carboxylic acid A is more acidic than carboxylic acid B. Suggest a
reason for this observation.
As shown in the drawing of A, the COOH group is close in space to the Cl, due to the rigid nature
of the bicyclo[2.2.1] ring system. Internal hydrogen bonding is possible in A, as indicated by the H----Cl
interaction, but such hydrogen bonding is not possible in B. Internal hydrogen bonding will weaker the
O—H bond, making it easier to react with the base, which leads to enhanced acidity for A relative to B.
In other words, carboxylic acid A has a smaller pKa (larger Ka) than carboxylic acid B.
H Me Cl
Me Cl O H
H
O O
H O
A B

11. Draw all resonance structures for those anions that are resonance stabilized and indicate which
are not resonance stabilized.
O
O S
O
O O
O
O Me O Cl O O Cl O
O O
(a) (b) O S (c) O (d) (e) N (f) O O
O O
O O
No Resonance
No Resonance
O No Resonance O Cl O O Cl O
O O O
O S
O
 Chapter 2 5

12. Alcohols are known to be amphoteric. Predict whether propan-1-ol will be an acid or a base or
will be neutral in the presence of each of the following:
(a) Sodium hydroxide (NaOH). The conjugate acid is water, which is slightly more acidic than
propan-1-ol, so propan-1-ol will likely react as a weak acid.
(b) Hydrochloric acid (HCl). The conjugate acid is chloride ion, and HCl is a much stronger acid
than propanol, so proposal will react as a base.
(c) Water (H2O). The conjugate acid is the hydronium ion, which is a much stronger acid than
propan-1-ol, so propan-1-ol will likely react as a very weak base or a very weak acid. For all practical
purposes, it is neutral.
(d) Ethanol (CH3CH2OH). The conjugate acid is an oxonium ion, which is a much stronger acid
than propan-1-ol, so propan-1-ol will likely react as a very weak base or a very weak acid. For all
practical purposes, it is neutral.
(e) Sodium amide (NaN2). The conjugate acid is ammonia, which is a significantly weaker acid
than propan-1-ol, so proposal will likely react as an acid.
(f) Butan-2-one. The conjugate acid is an oxonium ion, which is a much stronger acid than
propan-1-ol, so propan-1-ol will likely react as a very weak base or a very weak acid. For all practical
purposes, it is neutral.
(g) Methane (CH4). Methane is not acidic or basic, so there is no reaction at all with propan-1-ol,
so it is neutral.
(h) Sulfuric acid (H2SO4). The conjugate acid is hydrogen sulfate ion, and sulfuric acid is a much
stronger acid than propan-1-ol, so propan-1-ol will react as a base.

13. In a solvent that is not capable of hydrogen-bonding, maleic acid (A) is known to be more acidic
than fumaric acid (B). Explain!
Maleic acid (A) is more acidic because one carboxyl group is relatively close to the OH unit of a
second carboxyl group (they are on the same side of the molecule), so internal hydrogen bonding is
possible. Fumaric acid (B) is less acidic, in large part, because the two COOH units are on opposite sides
of the rigid alkene unit so internal hydrogen bonding is not possible. Note that there is no rotation about
the C=C unit.
O
H
O
O O
H H H
O O O
O
A B
6 Organic Synthesis Solutions Manual

14. Which of the following should react faster with BF3, trimethylamine or trimethylarsine
(Me3As)? Explain!
Trimethylarsine (Me3As) has the larger arsenic atom relative to nitrogen of trimethylamine, but it
is slightly less electronegative. In general, electronegativity and basicity decreases going down the
periodic table, so the electron density on nitrogen is more available, and it is the stronger base. This
means that trimethylamine will react faster with the Lewis acid, BF3.

15. Draw the product expected from a reaction of mercuric chloride (HgCl2) and dimethylamine.

Me HgCl2 Me
H N: H N HgCl2
Me Me

16. Give the products formed in each of the following reactions:

Br I
(a) (b) (c)
I
Br I

O HO
(d) (e) (f)
Cl

17. Briefly discuss why 2,3-dimethylbut-2-ene might react faster with HCl than with but-2-ene.
Draw the mechanism for both reactions as part of your answer.
2,3-Dimethylbut-2-ene reacts faster with HCl than does but-2-ene because this reaction is an acid-
base reaction, and the more highly substituted C=C unit in 2,3-dimethylbut-2-ene leads to a more electron
rich π-bond, which makes it a stronger base. In other words, 2,3-dimethylbut-2-ene will react faster with
HCl. In addition, the tertiary carbocation intermediate derived from 2,3-dimethyl-2-butene is more stable
than the secondary carbocation derived from 2-butene, and the increased stability should lead to a lower
activation energy and a faster reaction.
Cl

Cl
 Chapter 2 7

18. Give the major product of the following reactions.

The major product or products are shown in each case. No mechanisms are provided.

HCl Cl
(a) +
Cl
HBr
(b) Br

Br
Br2 , CCl4
(c)
H
Br
cat p-TsOH Via rearrangement of the
(d) initially formed 2° carbocation
EtOH , heat
OEt
Cl
HCl
(e)

I2 , CCl4 I
(f)

I
HOCl
Cl
(g)
aq THF
OH

Br2 , CCl4
(h) Br
Br
Cl
HCl Via rearrangement of the
(i) initially formed 2° carbocation

cat p-TsOH
(j) Via rearrangement of the
EtOH , heat initially formed 2° carbocation
OEt
8 Organic Synthesis Solutions Manual

19. Show a synthesis of 2,3-dibromo-2,3-diiodohexane from hex-2-yne.

Br I
1. I2 , CCl4

2. Br2 , CCl4
I Br

20. Give a complete mechanism for the following reaction:

O
cat H+ , H2O/ether

+ H+ Tautomerize

H H
OH
O
+ H2O - H+

H H
H

21. Give the complete mechanism for the following transformation.

Catalytic H+ , H2O

OH
- H+
+ H+

1,2-Methyl
shift OH2

OH2
 Chapter 2 9

22. Give the major product for each reaction.

O OTES
O
(a) (b)

HO Org. Lett. 2012, 14, 378

Org. Lett. 2012, 14, 1250 HO OTES

H H
(c) H H
O
O
J. Org. Chem. 2003, 68, 7143

OH