Chapter 1 1

CHAPTER 1
1. The calculations are shown for each molecule using values from Table 1.4 in Chapter 1.

NH2
NH2

NH2

A B

(a) H°A = ACHR2 + AC≡ = 2.1 + 0.2 = 2.3 kcal mol-1 If A + B = 1

H°B = ANHR + GC≡ + GCHR2 = 1.3 + 0 + 0.8 = 2.1 kcal mol-1 then, A = 1-B
B B
ΔH° = H°B – H°A = 2.1 – 2.3 = –0.2 kcal mol-1 Keq = A = 1-B
At 150°C, 2.303 RT = 2.303(1.987)(423)* = 1.936 kcal mol-1 Keq(1-B) = B
Keq
[* T is in Kelvin = °C + 273] and B = 1+K , via
eq
therefore, ΔG° = –0.2 = –1.936 log Keq 1.27(1-B) = B
-0.2
log Keq = -1.936 = +0.103 1.27 - 1.27B = B
Keq = 100.103 = 1.27 1.27 = B+1.27B
1.27
1.27 = B(2.27) 2.27
= B = 0.56
Therefore, 56% of B and 100-56 = 44% of A.

Since A has two axial groups and B has only one, an initial glance suggests that B will be lower
in energy and be the greatest contributor to the chair population. Conformation A has one axial group
(CHMe2) on the top and one axial group (C≡CMe) on the bottom so ACHR2 and AC≡ are used from
Table 1.4. In B there is only one axial group (NH2) so AOR is used. The two equatorial groups in B
(CHMe2 and C≡CMe) are on adjacent carbons, so there are two G terms, GC≡ and GCHR2.
2 Organic Synthesis Solutions Manual

Cl CH3
O
OMe
H3C O Cl
MeO
Cl H3C
MeO O
A B

3
(b) H°A = 4 (ACH2R + ACl) = 0.1.8 + 0.4 = 1.65 kcal mol-1 If A + B = 1
3 3
H°B = (AOR + GCH2R + GCl) =
4 4 (1.8 + 0.4 + 0.5) = 2.03 kcal mol-1 then, A = 1-B
B B
ΔH° = H°B – H°A = 2.03 – 1.65 = 0.38 kcal mol-1 Keq = A = 1-B
at 25 °C, ΔG° = 0.38 = -1.364 log Keq Keq(1-B) = B
0.38 Keq
log Keq = -1.364 = -0.279 and B = 1+K
eq
0.526
Keq = 10-0.279 = 0.526 1.526
= B = 0.345
Therefore, 34.5% of B and 100-34.5 = 65.5% of A.

Although B has two axial groups, it is actually lower in energy because the axial chlorine has a
lower interaction that the combined G value interactions in B. It accounts for only 35% of the
population of chair conformers. Conformation B has two adjacent and diequatorial groups, so GCH2R
and GCl are used from Table 1.4. Since B has one axial methoxy group, AOR is used.

Cl Me
OMe OMe

OMe OMe
MeO Me Cl
MeO
Cl OMe MeO Me
OMe
A B
(c) H°A = AOR + ACl + GCH2R + GOR = 0.8 + 1.8 + 0.4 + 0.2 = 3.2 kcal mol-1 If A + B = 1
H°B = UOR + UOR + ACH2R + GCl + GOR = 0.8 + 0.8 + 1.8 + 0.5 + 0.2 = 4.1 kcal mol-1 then, A = 1-B
B B
ΔH° = H°B – H°A = 4.1 – 3.2 = 0.9 kcal mol-1 Keq = A = 1-B
at 25°C, ΔG° = 0.9 = –1.364 log Keq Keq(1-B) = B
0.9 Keq
log Keq = -1.364 = –0.66 and B = 1+K
eq
0.22
Keq = 10-0.66 = 0.22 1.22
= B = 0.18
Therefore, 18% of B and 100-18 = 82% of A.
The three axial groups in B, along with the two G-interactions make it much more sterically
demanding than the two axial groups and the two G-interactions in A. Therefore, A accounts for the
greater percentage of chair conformations.
 Chapter 1 3

Ph
Me3C
Me3C Ph
Ph
A CMe3 B
(d) H°A = no interactions = 0 kcal mol-1 If A + B = 1
H°B = Aaryl + ACR3 = 3.0 + 6.0 = 9.0 kcal mol-1 then, A = 1-B
B B
ΔH° = H°B – H°A = 9.0 – 0 = 9.0 kcal mol-1 Keq = A = 1-B
at 25°C, ΔG° = 9.0 = –1.364 log Keq Keq(1-B) = B
9.0 Keq
log Keq = -1.364 = -6.598 and B = 1+K
eq
3x10-7
Keq = 10-6.598 = 3x10-7 1.00
= B =3x10-7
Therefore, 0.00003% of B and 100-0.00003 = 99.99997% of A.
Since A has two large equatorial groups and B has two large axial group, the equilibrium is
pushed in the direction of A, in essentially 100%.

2. The absolute configuration for each chiral center in the following molecules is shown beside the
appropriate chiral center.

H O
OH OH OH H
(R) (R)
(S) (R) OH N H
(S) (R) (S) (S) (R)
N (R)
(S)
(a) S OSO3- OH (b) (c) (R)
(S)(R)
(R)
(R)
HO (R) (S) HO (R) O
H O (S)
(S) (S)
HO OH O
Kotalanol Lepistine
(-)-Crinipellin A

3. Determine the absolute configuration for every stereogenic center in the following molecules:

O (R)
O
(R) (R) (S) N
(R)
O
(a) (E) (c)
(S)
(R)
(S) O (b) (S) N (R) (R)
(Z)
(E) (R) OH OH
(R) MeO2C (R)
O O (E)
O (R)
O O
(E)O (+)-Lapidilectine B
(S) see J. Org. Chem. 2004, 69, 9109
Amphidinolide X (S)
(S)
see J. Am. Chem. Soc.
2004, 126, 15970 O (E) (E)
(R) (S)
(E) (E) (E)
O Mycolactone C OH OH
see Org. Lett. 2004, 6, 4901
4 Organic Synthesis Solutions Manual

4. Draw both chair conformations and one twist-boat conformation for trans-1,2-
di(triphenylmethyl)cyclohexane.

CPh3 Ph3C
H
H
H H
CPh3 H
Ph3C
H CPh3 CPh3

5. Using the reaction wheel (Fig. 1.2) give reasonable syntheses, including reagents and all
intermediates (no mechanisms).
There is more than one "correct" answer. One possible solution is shown for each
transformation. The letters (a), (f), etc., beside each reagent refer to the lettered transformations from
Figure 1.2 in Chapter 1.

1. B2H6 OH
(a)
2. NaOH/H2O2

OH
RCO3H 1. NaCN , THF
(b) O
(v) 2. hydrolysis
(c)
CN

(c) dilute NaOH CrO3 , H+

Br OH CHO
(c) (a)

The first reaction is a poor one since elimination will be a major process. Limiting
the choices to those in Figure 1.1 is a problem since there are other ways to do this.

(d) PBr3 KOH , EtOH 1. O3 2. H2O2 CO2Me

OH Br
(d) (f) 2. SOCl2 ; MeOH CO2Me
(x), but there are no reactions shown for conversion to acid derivatives

O MeMgBr Me
(e) 1. O3 2. Me2S
OH
(3b)
(x)
see Table 1.1

(f) 1. H3O+
CN CONH2
2. SOCl2
3. NH3 No reagents are provided in Figure 1.1 since -
for the conversion to acid derivatives
 Chapter 1 5

6. Use the Compendium of Organic Synthetic Methods (Vol. 13) to give three different reactions
(with literature references and reactions) for each of the following.
There are potentially many examples for each part (but not always; see the last sentence for this
answer). This is a literature-searching question, and there are no correct or incorrect answers. The
appropriate sections and pages from Vol. 13 of the Compendium are indicated for each category.

(a) Acids from Nitriles. Section 28. Volume 13: p. 18 (1 example).

(b) Aldehydes from Nitriles. Section 58. Volume 13: p. 84 (0 examples).
(c) Amines from Halides. Section 100. Volume 13: pp. 283-290 (43 examples).
(d) Amides from Nitriles. Section 88. Volume 13: pp. 248-249 (6 examples).
(e) Ethers from Halides. Section 130. Volume 13: pp. 353-354 (28 examples).
(f) Halides from Amines. Section 142. Volume 13: pp. 369 (4 examples)
(g) Ketones from Olefins. Section 179. Volume 13: pp. 393-395 (14 examples).
(h) Olefins from Aldehydes. Section 199. Volume 13: pp. 419-421 (16 examples + 1 review).
The real lesson from this exercise, apart from learning to use this literature resource, is that some
functional group exchange reactions are well studied and there are many variations. Others yield only a
handful of possibilities. Despite the request for three examples in the question, 0 examples were found
for (b) and only 1 example was found for (a). In these cases, further literature searching in the older
literature is a necessity.

7. Draw molecule A in what should be the low-energy conformation. Briefly discuss the
conformation for the highlighted ring in molecule A. Also discuss the conformational preference
(axial or equatorial) for both methyl groups (1 and 2) as well as the hydroxyl.
The bicyclo[2.2.1]heptane unit (A) is very rigid and greatly influences the stereochemistry for
the molecule. The appended six-membered ring B assumes a conformation that is close to a twist-boat,
and it cannot 'ring flip' easily due to the conformationally immobile bicycloheptane unit. This constraint
forces the methyl group (Me2) into a pseudo-axial position. The other methyl group (Me1) is at a
bridgehead position of the bicycloheptane and is effectively perpendicular to that ring, as shown. The
hydroxyl group is formally in a pseudo-axial position relative to ring B.
Me2
Me2
H

HO
B
A

A
A
Me1 Me2
6 Organic Synthesis Solutions Manual

8. In each of the following disconnect the indicated bond and draw the disconnect products.
Assign d/a based on any natural bond polarization. If there is no bond polarization, assign a
reasonable d/a. Correlate the disconnect products with real reagents using the concept of
synthetic equivalents in Table 1.2.
Donor and acceptor sites are assigned based on known reaction types, and the reagents will
generate the requisite bond from those fragments. Other reactions may be required in some cases to
manipulate the functional group (e.g., reduction of the alkyne unit to a trans alkene in (b).

OH OH O
(a) d
a
MgBr H

(b) Br
a

d O Br
O O
(c) a

O
O O
CH3Br
d
(d)
• a

a CN
(e) d CN Br
CN
a

d Br
(f)

9. Determine the absolute configuration (R or S) for each chiral axis in the following molecules:
The R or S configuration for the chiral axis of each molecule that has a chiral axis rather, as well
as that of stereogenic centers chiral center, is shown for (a) - (e).

Cl Et
OMe CH2Cl H CHMe2
Cl H (S)
(S)
(R) O
(S) OH (r) (s)
(a) C (R) (b) (c) (d) (e)

NH2 (Z) (R)

Br CH2CH2Cl (R) NH
Me2HC CMe3 HOH2C OH
H Me
 Chapter 1 7

For (a), Cl is 1 and H is 2; Br is 3 and CH2CH2Cl is 4. For (b), OH is 1 and Caryl is 2; NH2 is 3
and Caryl is 4. For (c), Cl is 1 and Et is 2; Me is 3 and H is 4. For (d), CH2Cl is 1 and Et is 2; CMe3 is 3
and CHMe2 is 4. For (e) the epoxy O is 1 and CHMe2 is 2; OH is 3 and CH2OH is 4.

10. Determine the absolute configuration for each stereogenic center in the following molecules:
Et
Me
(R) OC O
H Me Me P
Me EtO (E)
O Me O
(S) Ph OiPr
Me Cp Fe (S)
Mg (S) (S) (R) (R)

O P Ar (R) O Ph
Br H Me Me (R) EtO2C
Ph3P
Me
(a) (b) Me (c) (d)

11. The conversion of the hydroxy-acid shown to the corresponding lactone is rather slow. When
pushed under aqueous acid conditions, epimerization at the carbon bearing the hydroxyl can
occur. Draw the lactone and explain the observations noted in this question.
When the hydroxy-acid cyclizes to form the lactone (see A) the two methyl groups are 1,3-
diaxial, with the tert-butyl group equatorial. In the presence of acid, the hydroxyl group can be
protonated and eliminate water and form a cation.
In the presence of water, the alcohol is regenerated, but both epimers are generated since reaction
with water leads to the methyl group being axial or equatorial in the lactone. Under equilibration
conditions, the lactone with one axial methyl and one equatorial methyl will be lower in energy due to
diminished A-strain, and the equilibrium will shift to favor that lactone (net epimerization of the
alcohol-bearing carbon in the hydroxy-acid). Acid catalyzed opening of the lactone gives, of course, the
hydroxy-acid.
Me
Me
H Me H
t-Bu O H
t-Bu O
H
Me O O O
H
A O B
8 Organic Synthesis Solutions Manual

12. Explain why cis-1,3-cyclohexanediol exists mainly in the diaxial conformation in aqueous
ethanol solution, when by Corey's ΔG calculations (see Table 1.4), the diequatorial conformation
should be lower in energy.
The diaxial conformation allows hydrogen bonding (see B). Such hydrogen bonding
counterbalances the energy difference of the diaxial (which has U-strain) vs. diequatorial conformations.
The net result is that although the diaxial conformation has U-strain, the hydrogen bonding makes it the
dominant species.

13. Determine the correct re/si label for each prochiral atom in the following molecules.

c c b
a si b
H Ph
O
(a) b
(b) a (c) N
re a N-H
c b OH
c a Ph
si
re

14. Draw the three most significant anti-rotamers of 1-phenylethan-1-ol (R = Me in the

accompanying diagram), and correlate them with the rotamers marked a-c on the energy curve.
The correlation is
OH H R ω
H H H H H H

• • ψ •
H R R OH HO H
C6H5 φ C6H5 C6H5

a (φ ~ 60°) b (φ ~ 300°) c (φ ~ 180°)

Taken from Eur. J. Org. Chem. 2004, 2398

15. (a) Draw the (2S, 3R,4R) and the (2S, 3S, 4S) derivative of molecule A. (b) Draw both the
erythro/threo and the syn/anti forms of molecule B.
OH 2 4 6
2 4 6
3 5 5
A 3 B
1 7
1 7
Br Cl
Br Br
2S, 3R, 5R erythro and syn
OH 6
2 4
2 4 6
3 5 A 5
3 B
7 1 7
1
Br Br Br Cl
2S, 3S, 5S threo and anti
 Chapter 1 9

16. Classify each of the following reactions as stereospecific/stereoselective and/or

regiospecific/regioselective.
(a) Diastereoselective (b) Enantiospecific (c) Regiospecific and diastereoselective.

17. Explain why the ground state energy of cyclodecane is higher than that of cyclooctadecane.
Why is cyclopentadecane higher in energy than cyclohexadecane?
Cyclodecane has a relatively small internal cavity where transannular interactions are
maximized. This transannular interaction disappears in cyclooctadecane where the additional carbons
make the internal cavity large enough for the "internal" hydrogen atoms to have little interaction.
Compare crown cyclodecane and cyclononane in the text, in Section 1.5.B. Inspection of Figure 1.23 of
the text can answer the second part of this question. Cyclohexadecane is an even-membered ring and, as
such, will fit better on the diamond lattice. Since cyclopentadecane has an odd-membered ring, there is
a "twist" in the ring when attempting to "lay it on the diamond lattice". This "twist" makes the energy of
the ring slightly higher.

18. Draw the boat conformation of cis-,trans-,trans-1,2,3,4-tetraisopropylcyclohexane.

H
H
H
H

See J. Am. Chem. Soc. 1994, 116, 10306