Chapter 3 1

CHAPTER 3
1. From the rate data given for compound A (in the table below), it is clear that the presence of a
methoxy group significantly enhances the rate of solvolysis of A. Offer a reasonable mechanistic
explanation of this solvolysis reaction that is consistent with the observed rate data.
Assume that differences in the rate, due to changing the leaving group, are insignificant for
this question.
This solvolysis reaction proceeds with loss of the leaving group to generate a cation. The
aromatic ring will stabilize that cation either by π-donation from the ring or by formal resonance
participation via a non-classical ion. In either case, an electron-donating substituent on the aromatic ring
will stabilize the charge and, thereby, stabilize the intermediate cation. This stability will be reflected in
the relative rate of the solvolysis reaction. Both OMe and Me are electron-donating and therefore
enhance the rate. Since OMe is a more powerful electron-donating group, the effect is large. The Cl
substituent is mildly electron withdrawing and, therefore, slows the relative rate by slightly destabilizing
the intermediate cation.
This problem is taken from J. Org. Chem. 1985, 50, 821.

2. Reaction of pentan-3-ol with potassium iodide in aqueous ethanol gave no reaction under
several different reaction conditions. If one adds a catalytic amount of para-toluenesulfonic acid,
however, the reaction proceeds to give 3-iodopentane. Explain these observations.
The OH group in pentan-3-ol is an extremely poor leaving group even though the iodide ion is a
good nucleophile, so an SN2 reaction is not facile. Despite the presence of the water, solvolysis of the
alcohol moiety to generate a 2° carbocation is extremely slow. If an acid catalyst is added, however,
protonation of the OH occurs and loss of water generates the cation. The cation is then trapped under
SN1 conditions by iodide to give 3-iodopentane.

- H2O + I–
H+
O
OH H I
H

3. Explain why the obvious SN2 conditions shown in the following reaction give only elimination
and no substitution with this secondary bromide.
This bromide is in fact a neopentyl-like molecule [R3C-CH(R')X] and, therefore, very sterically
hindered to nucleophilic displacement (see 3.2.1.1). Neopentyl halides react much slower with
nucleophiles under SN2 conditions than do tertiary halides. The use of KOH in DMF promotes
substitution, and the DMF does not allow facile ionization to give an SN1 displacement. Elimination
with the basic KOH dominates if the substitution reaction is too slow to compete.
2 Organic Synthesis Solutions Manual

4. Explain why the 14C label is found at both C1 and C2 in the aniline product despite the fact
that the label is localized on C1 in the chlorobenzene precursor. The * indicates the position of the
14C label.
Taken from Stock, L.M., Aromatic Substitution Reactions, Prentice-Hall, Englewood Cliffs, N.J.,
1968, p. 91. Formation of a benzyne intermediate (X) allows addition of NH2 to either carbon of the
triple bond, so the 14C label is on both carbons relative to the ipso carbon bearing the amine unit.

Cl H2N * NH2 NH2

* H2O *
+ *

* = 14 C
X

5. Does the molecule shown undergo an E2 reaction? If so, draw the major product(s). If not,
why not?
This cyclohexane derivative exists in two chair forms, A and B. An E2 reaction cannot occur via
A because the Br is equatorial and trans-diaxial relationship (anti) between Br and any β-H(s) is
impossible. In B, the Br is axial and only one β-H is axial. Therefore, an E2 reaction can give only one
alkene with the double bond toward the methyl group rather than the ethyl group. The stereochemistry
in the halide and conformational constraints of the E2 reaction makes this a regiospecific elimination.

Me Me Br Me
H H
Br Me Me
Et Br H Me
Me H
Et A Me B Et Et

6. 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. The mechanism shown is the one 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
OH H
SN1-like
O Tetrahedron Lett. 2000, 41, 3411
 Chapter 3 3

7. Treatment of alcohol A leads to B in 70% yield. Explain this product in terms of a mechanism
and comment on why the C=C unit is generated between C2-C3 rather than between C2-C1 [hint,
see Section 10.3.2].
See Tetrahedron Lett. 2000, 41, 403. This reaction proceeds by protonation of the alcohol and
loss of water from A to form a carbocation 1. There are two potential sites for rearrangement to a
tertiary cation, to 2 or to 3. To form cation 3 requires that the sp2 carbon be flattened to a trigonal
planar shape. This would subject the tricyclic system to a great deal of strain, and the result is that
cation 2 is formed preferentially. Loss of a proton via an E1 mechanism leads to the alkene product, B.

H OH H

p-TsOH , Benzene
Reflux
H 70% – H+
H
H
A B

+ H+ ; – H2O Lower in energy

H

H
2

High energy due

to flattening the
H tricyclic ring system H
so it is less favorable

1 3

8. Suggest a mechanism for the following transformation.

This reaction is taken from Org. Lett. 2003, 4, 59. Initial deprotonation of the alcohol leads to
the alkoxide shown. As the carbonyl of the aldehyde is formed, the bonds are properly oriented so that
formation of the C=O unit of the aldehyde ruptures the adjacent bond, forming the fused four-membered
ring by transannular displacement of the bromide.

O O
O
Br KH Br
H H
CHO
OH O
4 Organic Synthesis Solutions Manual

9. Explain each of the following.

(a) This is the Hofmann elimination reaction (3.7.1) and demands a syn transition state (an
eclipsed conformation for reaction). Because of the requirement for an eclipsed conformation (where
the leaving group on the β-carbon and the "base" can be in close enough contact) the lowest energy
eclipsed conformation will lead to the major product. In this case, the lowest energy transition state is A
rather than B, and ethene is the major alkene product, not 4-methylpent-2-ene. The i-Pr↔Me
interaction in B destabilizes that conformation relative to the H↔H interactions in A. In both A and B,
the NR3↔H interactions are about the same.
NEt2C4H9 NEt3
H H

• •
H H
H H H Me H
A Me B

(b) Taken from J. Org. Chem. 2004, 69, 7616. The strongly electronegative fluorine atoms
withdraw electron density, making the C=C unit very electrophilic. This inductive effect makes the
alkene carbon more susceptible to attack than the epoxide carbon, despite the fact that there is modest
steric hindrance. One epoxide carbon is also sterically hindered. Such attack drives the SN2' reaction to
the allylic alcohol shown, as a mixture of E and Z isomers.
OH
Li Ph
F O
Ph
F F
Workup as a 2nd step Bu E+ Z
F

(c) Displacement of the iodide is an SN2 reaction, and inspection of the pentacoordinate
transition state shows that these two neutral reactants produce a charged transition state where a positive
charge builds on the nitrogen (not on carbon) and a negative charge builds on iodine (see A).
Separation of these two charges (water promotes separation of charges) favors formation of the final
products since the carbon is transferred to the positive nitrogen, with iodide as the counter-ion. This
contrasts with transition state B, the "normal" Walden inversion that arises when a charged nucleophile
attacks a neutral substrate. Water as a solvent will separate charges and promote ionization. Separation
of charges in B will slow the reaction since the incoming charged nucleophile is separated from the
developing charge on the central carbon. In A, however, separation of positive and negative charges
favors product formation. For this reason, the reaction of an amine and a halide to give an ammonium
halide is faster in aqueous media than in non-aqueous media (which cannot separate charges).
C3H9 R
δ+ δ− δ− δ+ δ−
Et3N C I X C I
H H R R
A B
 Chapter 3 5

10. 3-Bromo-4-methylhexane is drawn in two different orientations, A and B. Using an E2

reaction, remove Ha from both A and from B and convince yourself that the two orientations lead
to the same alkene. Explain this selectivity, and also explain why an E2 reaction leads to one
alkene but an E1 reaction leads to a mixture of (E) and (Z) isomers.
3-Bromo-4-methylhexane reacts with hydroxide (a base for an E2 reaction) by removing Ha.
The orientation of the molecule does not matter because the important feature is the anti-relationship of
the Br and Ha. When Ha is removed, the transition state for the E2 reaction will retain the
stereochemical relationship of the groups. Since the two ethyl groups are on the same side in the anti-
orientation, they will be on the same side in the transition state, and this will lead to cis-3-hexene as the
major product, with the two ethyl groups still on the same side. If this reaction were carried out under
E1 conditions, ionization of the bromine would lead to planar carbocation C, and removal of Ha could
occur from either face since the bond to the carbon bearing Ha is free to rotate. This leads to scrambling
of the stereochemistry and a mixture of cis- and trans-alkenes.

Me
5 6
Br Me H
3

H 4 Ha
Ha
2 H Me Rotation about this bond
1 A leads to a mixture of
OH
cis- and trans-alkenes
1
2
Ha
H 3 4

6
Br Me 5
B

11. Offer a mechanistic explanation for the following transformation.

See J. Org. Chem. 1997, 62, 641.
6 Organic Synthesis Solutions Manual

12. Offer a mechanistic explanation for the following transformation.

This sequence is taken from Org. Lett. 2003, 5, 3361. The alkene unit reacts with iodine to give
the diiodide in situ, and the proximal iodide is displaced by the amine in an internal SN2 reaction to give
the bicyclic amine. A second internal SN2 reaction displaces the remaining iodide to form an
aziridinium iodide. The nucleophilic iodide ion attacks the methyl group of the ester, displacing the
carboxylate group, and the electron flow is such that the oxygen opens the aziridinium ion to form the
lactone unit in the product.

t-BuMe2SiO Me t-BuMe2SiO Me
Me Me
I2 , CH2Cl2/ether

t-BuMe2SiO CO2Me rt , 2 d t-BuMe2SiO CO2Me

NH NH I I

t-BuMe2SiO Me
t-BuMe2SiO Me
H
H Me t-BuMe2SiO
N Me
t-BuMe2SiO
N CO2Me O
I I
t-BuMe2SiO Me
H3C O

t-BuMe2SiO H
N Me
H O
O

13. For each of the following give the major product, with all appropriate stereochemistry. If
there is no reaction, indicate by N.R.

Et Et MeCH2O OSiMe2t-Bu

(a) (b) (c)

C3H7 N OPMB
HO O O OH
Me
note inversion of configuration
Via OH → Br followed J. Org. Chem. 2003, 68, 8129 at the site of ether formation
O
by internal S N2 by nitrogen see Eur. J. Org. Chem. 2000, 1889
J. Org. Chem. 2003, 68, 4371
N CH2OMe
HO HO
OCH2Ph
H N
N O
H
(d) CH2OMe (e) Et (f)
NH
PhH2CO N
J. Am. Chem. Soc. N NHCH2Ph
O 2002, 124, 3939 H
Me
OCH2Ph J. Am.Chem. Soc. 2002, 124, 4628 J. Am. Chem. Soc. 2002, 124, 8584
 Chapter 3 7

Br

(g) (h) (i) C12 H25

N OCH2OCH2CH2OMe
BnO
THPO CO2t-Bu OH

J. Org. Chem. 2003, 68, 6905 J. Org. Chem. 2003, 68, 6279 J. Am. Chem. Soc. 2004, 126, 36

H
OCH2OMe Br H
(j) (k) (l) O
NC
O O

OH
Org. Lett. 2002, 4, 937 J. Nat. Prod. 2002, 65, 909 J. Org. Chem. 2004, 69, 1744
CO2Me
PhH2CO MeO
O
CN O
(m) (n) N (o) H
O
Me Et
HO N
OMe Me
HO
H

J. Org. Chem. 2003, 68, 7422 J. Org. Chem. 2004, 69, 2191 J. Chem. Soc., Perkin Trans. 1 2001, 2398
HO Me
OMe HO
MeO
O
(p) (q) (r)
AcO N3 Me
Me O
Br OH
AcO OAc Me
Org. Lett. 2001, 3, 3353 Tetrahedron Lett. 2000, 41, 2573 see Tetrahedron Lett. 2000, 41, 1151

O
MeO MeO TBSO SiMe 3
(s) (t) (u)
N BnO

Me
see J. Org. Chem. 1993, 58, 2186 J. Am. Chem. Soc. 2001, 123, 3214 J. Am. Chem. Soc. 2005, 127, 5596
8 Organic Synthesis Solutions Manual

14. For the reaction shown, (a) Draw the transition state (b) Give the major product
(c) What type of reaction is this?
(a) The transition state is shown in brackets. Hydroxide removes the β hydrogen only when that
hydrogen is in a conformation that places it anti to the leaving group (here, bromine). In this transition
state, the relative positions of the groups are fixed and this is translated to the alkene, where a single
product is formed. The reaction is, therefore, stereospecific.

Rotate Me
Me Et Et
Me Br Me
Et H Br
Et H Br
- HBr Et
H H
H Br H
Me H
Ph H H Ph
Ph Ph Ph –OH

(b) The major product is trans-1,2-diphenylprop-1-ene. (c) This is an E2 reaction.

15. In each case, predict the major product and explain your answer.
O OAc Me
Ph Ph
Me
(a) (b) MeO (c) (d) (e)
CO2H

OH NC OH

(a) The most acidic hydrogen is the phenolic hydrogen (pKa ≈ 10) vs. pKa ≈ 17 for the primary
alcohol. Deprotonation gives the phenoxide, which reacts with iodomethane to give the anisole
derivative shown.
(b) Two molar equivalents of base deprotonate both the carboxyl first (most acidic) and the
alcohol second (least acidic). Of the two anions, the carboxyl anion is resonance stabilized and less
nucleophilic than the alkoxide, where the charge resides almost entirely on oxygen. Since the alkoxide
oxygen is more nucleophilic, it will react preferentially with one equivalent of allyl bromide to give the
ether shown.
(c) There are two leaving groups in this molecule that can be displaced by the nucleophilic
cyanide in an SN2 reaction. The mesylate group is a much better leaving group than acetate. For this
reason, one expects the cyanoacetate product shown to predominate rather than the alternative
cyanomesylate.
(d) The dianion shown has a carbon nucleophile and an oxygen nucleophile. The carbon
nucleophile is more nucleophilic, despite the fact that it is resonance stabilized by the adjacent phenyls.
The product will therefore be the methylated derivative shown. Since the nucleophilic strength of the
carbanion is diminished by resonance, some alkoxide may be formed.
(e) In this case, the primary iodide is treated with base. Normally, primary iodides undergo
elimination slowly, and substitution predominates when a nucleophilic base is used. In this case,
however, DBU is a non-nucleophilic base, and reaction will give the alkene shown as the major product.
 Chapter 3 9

(f) The product is that shown. Initial formation of the enolate anion and quenching with PhSeCl
generated the phenylselenide. Oxidation with hydrogen peroxide gave the selenoxide in situ, which
eliminated spontaneously to give the alkene unit in the conjugated lactam product.
t-BuO2C
N OSiPh2t-Bu J. Am. Chem. Soc. 2002, 124, 14826
O

16. For the following reaction, predict the product and show the correct stereochemistry. Use
Newman projections to indicate how you chose your product and to justify your answer.
The product is the less substituted alkene (4,6-dimethylhept-2-ene, C) via syn elimination of an
intermediate sulfoxide. The syn elimination demands an eclipsed transition state, and the two pertinent
eclipsed conformations where a β-hydrogen can be removed are A and B. From these Newman
projections, A (for removal of Ha) is less sterically hindered due to decreased torsion strain than is B
(for removal of Hb). For this reason, A will have a higher population at a lower energy and will account
for the major product, C. Note that C is shown as a mixture of cis and trans isomers, despite the fact
that the starting iodide contained a stereogenic center. Removal of the two Ha's in A will lead to the
isomeric mixture of alkenes, C.

Ha Hb
O Ph O
S Ph
Ha S
H

Hb H • • Hb
S Me Me
H CHb(Me)C5H11 CHHaMe
O Ph H C
H C5H11
A B

17. For each of the following, show the major product. Explain your choice.
(a) The Fischer projection for the starting material represents a chiral, non-racemic bromide.
Once the bromine and β hydrogen are in the proper anti conformation, the base removes the hydrogen
and expels the bromine. The other groups are fixed in this transition state, leading to trans-2-phenyl-3-
methyl-pent-2-ene.

HO–
Me H
(S) H Me KOH Et Me
Ph Br Ph EtOH Me
(R) Ph
(R) (S)
Et H Et heat
Me Br Et Me Ph
Me Me
Br
10 Organic Synthesis Solutions Manual

(b) This cyclohexane derivative exists as an equilibrium mixture of A and B. For an E2 reaction,
the bromine and a β hydrogen must be trans and diaxial. In A, the bromine is equatorial, so there is no
chance for elimination. In B, the axial bromine is axial to two axial hydrogen atoms. Elimination will
therefore lead to a mixture of two regioisomeric products, C and D.

Br Br
Et Et Me Et Me
Et Me Me Et

Br H Me
H
A B C D
(c) In this example, the cyclohexane bromide also exists as A and B, and A cannot react via an
E2 reaction because the bromine is equatorial. In B, however, only the hydrogen attached to the methyl-
bearing carbon is trans and diaxial with the bromine, so there is but one product, C.

Br Br
Me Me Et
Me Et Me

Br H H
Et
Et
A B C

18. For each of the following provide a suitable synthesis. Show all intermediate products and all
reagents.
Br Br
CHO
a b, c

(a) CBr4 , PPh3 (b) BuLi (c) MeI

(a)

(b)
NHAc NH2
NO2 NO2 NH2 NHAc

a b c d e f

Cl Cl
Cl Cl Cl
SO3H SO3H
(a) HNO3 /H2SO 4 (b) Cl2/AlCl3 , heat (c) H2 , Pd/C (see Sect.. 7.10.E) (d) Ac2O (e) SO3 /H2SO 4 (f) aq acid
 Chapter 3 11

NO2 NH2 OH

a b c d

(c) + ortho
Cl (separate)
Cl Cl Cl
(a) Cl2 , AlCl3 (b) HNO3 , H2SO 4 (c) H2 , Pt (d) NaNO2 , HCl ; H2O (reflux)

NO2 NH2 OH
NO2
a b c d

Br Br Br
(a) HNO3 , H2SO 4 (b) Br2 , AlCl3 (c) H2 , Ni (d) NaNO2 , HCl ; H2O (reflux)
(d)

OH OH
a b
O
CN CN
(a) 1. NaCN , THF 2. aq acid (b) 1. PhCO2Na , PPh3 , DEAD 2. saponify
(e)

OH
OEt
a b

(a) aq H2SO 4 (b) 1. NaH , THF 2. EtI

(f)

OH Et
a
(a) 1. NaH 2. CS2 3. MeI 4. 200°C

(g)