Chapter 1

CHAPTER 1
1. The calculations are shown for each molecule using values from Table 1.5 in Chapter 1.
CHMe2

NH2

NH 2

Me2 HC
C
C-CH3

C
CMe

NH2

C
CMe

Me2 HC

(a) HA = ACHR2 + AC = 2.1 + 0.2 = 2.3 kcal mol-1

If A + B = 1

HB = ANHR + GC + GCHR2 = 1.3 + 0 + 0.8 = 2.1 kcal mol-1

then, A = 1-B

H = HB HA = 2.1 2.3 = 0.2 kcal mol-1

B
B
Keq = A = 1-B

At 150C, 2.303RT = 2.303(1.987)(423)* = 1.936 kcal mol-1

Keq(1-B) = B

[* T is in Kelvin = C + 273]

Keq
and B = 1+K , via

therefore
G = 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

eq

1.27 = B(2.27)
1.27
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 (CCMe) on the bottom so ACHR2 and AC are used from Table 1.5. In B there is only one axial
group (NH2) so AOR is used. The two equatorial groups in B (CHMe2 and CCMe) are on adjacent carbons, so
there are two G terms, GC and GCHR2 .
CH3

Cl
H 3C
MeO

MeO

O
Cl

Cl
A

OMe

H3 C
B

(b)

Organic Synthesis Solutions Manual

3

HA = 4 (ACH2R + ACl) = 0.1.8 + 0.4 = 1.65 kcal mol-1

3

HB = 4 (AOR + GCH2 R + GCl) =

3
4

If A + B = 1

(1.8 + 0.4 + 0.5) = 2.03 kcal mol-1

then, A = 1-B

H = HB HA = 2.03 1.65 = 0.38 kcal mol-1

B
B
Keq = A = 1-B

at 25C,
G = 0.38 = -1.364 log Keq

Keq(1-B) = B
Keq
and B = 1+K

0.38

log Keq = -1.364 = -0.279

eq

0.526
1.526 = B = 0.345

Keq = 10-0.279 = 0.526

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 1.5. Since B
has one axial methoxy group, AOR is used.
Cl
MeO

Me

OMe
OMe

OMe

MeO

Cl

Me
OMe

Cl
MeO

(c)

OMe
OMe
Me
B

(c) HA = AOR + ACl + GCH2R + GOR = 0.8 + 1.8 + 0.4 + 0.2 = 3.2 kcal mol-1

If A + B = 1

HB = UOR + UOR + ACH2 R + GCl + GOR = 0.8 + 0.8 + 1.8 + 0.5 + 0.2 = 4.1 kcal mol-1

then, A = 1-B

H = HB HA = 4.1 3.2 = 0.9 kcal mol-1

B
B
Keq = A = 1-B

at 25C,
G = 0.9 = 1.364 log Keq

Keq(1-B) = B

0.9
log Keq = -1.364 = 0.66

Keq
and B = 1+K

Keq = 10-0.66 = 0.22

0.22
1.22 = B = 0.18

eq

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

Ph
Me3C

Me3C

Ph

Ph
A

CMe3 B

HA = no interactions = 0 kcal mol-1

(e)

If A + B = 1

HB = Aaryl + ACR3 = 3.0 + 6.0 = 9.0 kcal mol-1

then, A = 1-B

H = HB HA = 9.0 0 = 9.0 kcal mol-1

B
B
Keq = A = 1-B

at 25C,
G = 9.0 = 1.364 log Keq

Keq(1-B) = B

9.0
log Keq = -1.364 = -6.598

Keq
and B = 1+K

Keq = 10-6.598 = 3x10-7

3x10-7
-7
1.00 = B =3x10

eq

Therefore, 0.00003% of B and 100-0.00003 = 99.99997% of A.

Since A has two large equatorial groups and B have 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.

OH
HO

HH

(a)
H

3.

(b)

Br

O
(+)-absinthin
see J. Am. Chem. Soc.,
2005, 127, 18

(c)

H
HH O
O

O H

O
O
H
biepiasterolide
see J. Org. Chem.,
2004, 69, 9100

H
OAc
(+)-laurencin
see Org. Lett., 2005, 7, 75

Organic Synthesis Solutions Manual

(a)
O

O
O

(c)

(b)

O
O

OH

OH

ON

N
MeO2C

(+)-lapidilectine B
see J. Org. Chem., 2004, 69, 9109

amphidinolide X
see J. Am. Chem. Soc.,
2004, 126, 15970

O
mycolactone C
see Org. Lett. 2004, 6, 4901

OH

OH

4. After donor and acceptor sites for disconnect fragments 22 and 23, fragment B represents an umpolung reagent
(acyl anion equivalent - see Chap. 8, Sec. 8.6.B), F. Fragment A is simply the alkyl halide,

22

23

AND
Br

CuLi Cl
2

S
S

O
G

E. The other d/a combination is C (which is the equivalent of organocuprate, G) and D (which is the equivalent of
acid chloride H). Both are viable processes but we not will choose the reaction of E and F since alkylation of
dithiane reagents can be sluggish (see Chap. 8, Sec. 8.6.B.ii) and because an extra step is required to convert the
dithiane back to the carbonyl (see Chap. 7, Sec. 7.3.B.ii). Acid chloride H contains

Cl

HO
O

O
H

OH
J

the four carbons of the starting material, and it is obviously derived from isobutyric acid (I), available from Aldrich
(2000-2001), $25.50/L. Assume it must be made from 2-methylpropene, however. According to Figure 1.1, one
route to an acid is by oxidation of an alcohol (see Chap. 3, Sec. 3.2.A). The alcohol (J) can be prepared from the
alkene by hydroboration (see Chap. 5, Sec. 5.4.A).

Once acid chloride H is available, it is reacted with

organocuprate G, derived from bromide E. In this analysis, E is not formally prepared from 2-methylpropene
(although a synthesis could be designed if desired), and G is considered to be a reagent in this synthesis (an 'off the

Chapter 1

shelf' compound that is reacted with the molecules derived from the retrosynthesis, just like B2H6 or CrO3 in the
sequence shown). If the reagents provided in this synthesis are not familiar, careful reading of the remainder of this
book and the literature will explain these choices.
5. 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 1.1 in Chapter 1.
(a)
OH

1. B2 H6

(w)

2. NaOH/H2 O2

1. NaCN , THF

(b)

RCO3 H
(v)

O
2. hydrolysis
(c)

C
N

CrO3 , H+

dilute NaOH
Br

(c)

OH

OH
CHO
(a)
(c)
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.

OH

PBr3

(d)

(d)

KOH , EtOH
Br

1. O3 2. H2 O2
2. SOCl2 ; MeOH

(f)

CO2 Me
CO2 Me

(x) & no reactions for conversion to acid derivatives

(e)

1. O 3 2. Me 2 S
(x)

1. H3 O+

(f)

CN

2. SOCl2
3. NH3

O MeMgBr
(3b)
see Table 1.1

CONH2

Me
OH

No reagents are provided in Figure 1.1 they are part of the conversion to acid derivatives

6. 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. 11 of the Compendium are indicated for each category.
(a) Acids from Nitriles. Section 28. Volume 11: p. 15 (0 examples).
(b) Aldehydes from Nitriles. Section 58. Volume 11: p. 103 (0 examples).
(c) Amines from Halides. Section 100. Volume 11: pp. 289-294 (28 examples).

Organic Synthesis Solutions Manual

(d) Amides from Nitriles. Section 88. Volume 11: p. 257 (5 examples).
(e) Ethers from Halides. Section 130. Volume 11: pp. 347-348 (6 examples).
(f) Halides from Amines. Section 142. Volume 11: p. 369 (0 examples)
(g) Ketones from Olefins. Section 179. Volume 11: p. 409 (3 examples).
(h) Olefins from Aldehydes. Section 199. Volume 11: pp. 440-443 (17 examples).
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, no examples were found for (a), (b) or (f). In
this case, further literature searching in the older literature is a necessity.
7.

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.
Me

Me2

HO
B

A
A

Me2

Me
1

8. For each molecule, a representative model from the indicated perspective using Spartan is shown.
1

(plus 'top' [above page] and 'bottom [below page] views)

4
AcO
(+)-mycoepoxydiene
3 see J. Org. Chem., 2004, 69, 8789

Chapter 1

top view

bottom view

2H
(b)

3
N

halochlorine
see J. Org. Chem., 2004, 69, 7928

O
OH

1
Cl
(plus 'top' [above page] and 'bottom [below page] views)

top

3
bottom

The purpose of this drawing exercise is to cast yourself in the role of a reagent approaching a molecule.
Different angles of approach means the reagent "sees" a different set of groups and atoms for each portion of the
molecule, which will have an important effect on the reactivity of the incoming reagent. By drawing the molecule

Organic Synthesis Solutions Manual

from several perspectives, the goal is to see how angle of approach and topography may influence reactivity in a
given molecule. Also, it emphasizes that the two-dimensional drawings we usually use often have little meaning in
terms of the real structure of a molecule and determining its reactivity.
9. 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

OMe

Et

CH2 Cl

Cl

CHMe 2

O
C

(a)

OH

(b)

Br

(d)

(c)

NH2

CH 2CH2 Cl

(e)

NH
H

Me 2 HC

Me

CMe3

HOH2 C

OH

For (a), Cl is 1 and H is 2; Br is 3 and CH2 CH2Cl 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), CH2 Cl is 1 and Et is 2; CMe3 is 3 and CHMe2 is 4. For (e)
the epoxy O is 1 and MHMe2 is 2; OH is 3 and CH2OH is 4.
Et

Me
Me

H Me

Br

Me

Ph
P

Me Me

(a)

(b)

OC

Me

Mg

10.

Me

R
Me

Ar

Cp

Me
Fe

EtO

O
O

EtO2 C

Ph3 P

OiPr

(c)

Ph

(d)

11. When the hydroxy-acid cyclizes to form the lactone (see A) the two methyl groups are 1,3-diaxial, with the tertbutyl 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 re-formed, 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
t-Bu
H
Me

Me
Me

H
t-Bu

O
A

O
O

H
O

12. The diaxial conformation allows hydrogen bonding (see B ). Such hydrogen bonding counterbalances the

Chapter 1

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.

(a)

c
re

13.

c si b
H
b
(b)a
re
OH
c
a

a
O

b
Ph

(c)

N
a N-H
Ph
si

14. The correlation is

Taken from Eur. J. Org. Chem. 2004, 2398
OH
2

2
3

Br

2 S, 3 R, 5R

OH
2
1

15.
16.

Br

Br

Cl

ery th ro and

s yn

Br

Br

4
5

Br

Cl

threo

an d

an ti

2S, 3S, 5 S

(a) diastereoselective

(b) enantiospecific

(c) regiospecific and diastereoselective.

17. 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" hydrogens to have little interaction. Compare 182B and 184 on in the text. Inspection of
Figure 1.13 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.

10

Organic Synthesis Solutions Manual

H
H
H

18.

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