IFM/ Kemi

Stefan Svensson
2007-04-23

Compendium
On
Problems in Physical-Organic Chemistry

Page

1
4
6
8
13
16
18
20
26

(Nr of problems)

Part 1:
Part 2:
Part 3:
Part 4:
Part 5:
Part 6:
Part 7:
Part 8:
Table:

General problems
Acids- Bases
Hammett Relationships
Orbital Symmetry reactions
Problems related to Nucleophilic Substitutions
Problems related to Elimination reactions
Problems related to Addition reactions
Miscellaneous problems
Hammett realationships

(14)
(11)
(10)
(17)
(20)
(12)
(11)
(25)

Most of the problems can be considered as self-studying problems, but some of them may
need further explanation.
Problems marked with * are considered to be more advanced.
A solution guide supports the compendium.

(When printing use layout 2 pages/page for environmental reasons!)

IFM/ Kemi
Stefan Svensson
20020423

Problems in Physical-Organic Chemistry

Part 1:
1.1

General problems

Predict the most stable conformation for each of the following molecules and explain
the basis of your prediction.
C(CH3)3

CO2CH3

OH

(a)

Cl
JACS 91(7020)1976

C(CH3)3

(b)

JACS 92(51510)1970

1.2. a) One of the diastereomers of 2,6-dimethylcyclohexyl benzyl ether exhibits two

doublets for the benzylic protons in its NMR spectrum. deduce the stereochemistry of
this isomer.
JACS 97(5178)1975
b) The NMR spectrum of the highly hindered molecule trimesitylmethane indicates that
there are two enantiomeric spieces present in solution, the interconversion of which is
separated by a barrier of 22 kcal/mol. Discuss the source of the observed chirality of
this molecule.
JACS 96(2165)1974
1.3

Azulene. an isomer of naphtalene, is categorised as a nonbenzoid aromatic compound.

Azulene

a ) From examination of its structural formula, why would you expect azulene to be
aromatic?
b ) Azulene has a dipole moment of 1.08 D. Draw resonance structures as a basis for
assigning a direction to the dipole.
1.4 * Consider following equillibrium data for 2-halocyklohexanones i two different solvents.
O

Halogen
Br
Cl
F

% Axial (Heptane)
85
76
48

% Axial (1,4-dioxane)
62
37
15

1.5

1.6

Oxidation of isopropyl alcohol to acetone by acidified dichromate occurs via formation

of a chromate ester. The rate of reaction was found to be first order in acid chromate ion
(HCrO4 ), alcohol, and hydrogen ion. The deuteriated compound (Me2CDOHCH3) was
found to react more slowly than the isotopically normal compound. Suggest a
mechanism for this reaction.
Which reaction in each pair has the larger negative entropy of activation ?
a)

COOMe

+
COOMe
COOMe

COOMe

b)

i
ii

c)

ii
CH3I

OC2H5

CH3OC2H5

(CH3) 3CCH2I + OC2H5

+I

(CH3) 3CCH2OC2H5 + I

CH3I

NH3

CH3NH3

+I

ii

CH3I

NH2

CH3NH2

+I

1.7 Indicate whether the relationship in each of the following pairs of compounds is identical,
enantiomeric, or diastereomeric:
a)

b)

CHO
H
NH2
HO
H
CH2 OH
H

CH2 OH
H
OH
H
NH2
CHO
H3 C

CH3

d)

CH3

CH3

e)

H
Cl

Cl
H
O

c)

f)

H
Cl

1.8

Ph
CH3

H
H

Cl

CH3
Ph

The structure orginally proposed for cordyceic acid, []D= +40.3o, has been shown to
be incorrect. Suggest a reason to be skeptical about the original structure, which is
given below:
COOH
HO

OH
HO

OH

1.9

Indicate which of the following molecules are chiral and which are achiral.
For each molecule that is achiral, indicate the element of symmetry that is present in
the molecule

(a)

CH3

H3 C

(b)

H3 C

(c)

CH3

H 3C

(f)

(e)

(d)
CH3
CH3

H3C

1.10

Suggest an explanation for the following observations:

a ) The dipole moment of the hydrocarbon calicene (see structure below) has been
estimated to be as large as 5.6 D.
b ) The measured dipole moment of p-nitroaniline (6.2 D) is larger than the value
calculated using empirical group moments (5.2 D).
c ) The dipole moment of furan is smaller than and in the opposite direction from that of
pyrrole.
(JACS, 94 (8851)1972)

a)

_
c)
Calicene

0.71 D
O

N
H

1.80 D
_

1.11. In the reaction profile below, which of the labels A, B, C, and D correspond to the
kinetic product, the thermodynamic product, an intermediate, and a transition state?

1.12 When some salts are dissolved in water, the water cools as a result. Why might this be?
Why, in that case, does the salt dissolve at all?

1.13 Which of the following sets of curly arrows show the imaginary movement of electrons
in resonance structures, and which show real movement of electrons in reactions? Draw
the alternative resonance structures/reaction products to which they lead.

1.14 Mevalonic acid readily forms a lactone, but this is not the only lactone it could form.
What is the alternative lactone, and why does it not form?
HO

OH

Mevalonic acid
HO

Part 2:
2.1

CH3 O

Acids- Bases

Provide an explanation for the relative acidities of the following phenols:

H3C
O2N

>

OH

O2N

OH

>

O2N

H3C

OH

H3C

2.2

The pKa value for m-nitrophenol is 9.3, and that for the para isomer is 7.2.
Provide an explanation for the difference in effect of the para and meta nitrogroups.

2.3

Would you predict oxazole to be more or less basic than pyrrole?

Oxazole

2.4

Pyrrole

Predict which member of each of the following pairs is the stronger acid.

a) m- and p-cyanophenol
b)

OH

c) NCCH2 CN
d)

and
and

CO2CO2H

and

e)
OH

F2 CHCH2 OH and CH3 CF2 OH

f)

NCCH2 CH2 CN
CO2-

and
O

g)

OH

and
N
H

CO2H

OH

N
H

2.5*

Predict the energetically preferred site of protonation for each of the following
molecules and explain the basis of your prediction.

a) PhCH

O
b) CH3C NHCH3

N Ph

c)

d)
N
H

JACS 85(724)1963

NH2

2.6*a) In H2O, phenol (pKa 10) is about 6 pKa units less acidic than aliphatic carboxylic
acids such as acetic acid (pKa 4). In the gas phase, phenol and acetic acid have
comparable acidities. Why?
b ) In H2O, acetic acid (Ka = 1.8x10-5) is about three times more acidic than the
pyridinium ion (Ka = 6.2x10-56. In MeOH ( = 34), the relative acidities are reversed.
The pyridinium ion dissociates about the same amount in both solvents (Ka = 2.8 x 106 in MeOH), but acetic acid dissociates almost 105 times less in MeOH (Ka =
2.2x10-10). Thus in MeOH, the pyridinium ion is some 104 more acidic than acetic
acid. Explain the reversal.
2.7

Which is the stronger acid of the following pair and why ?

( b ) COOH
(iii) ( e ) COOH
( a ) COOH
(i)
COCH3

CH3

( c ) COOH

(d)

(iv)

COOH

(g) COOH
COOH

2.8

and

CH2
COOH

NO2

(i) CH3COOH

COCH3

( h ) COO

and

CH2

and

(v)

COOH

and

and

(ii)

(f)

(j) HOCH2COOH

Discuss the pKa valus of the carboxylic acids given. (A lower pKa indicates a stronger
acid.)
a)
CH3 COOH

c)

d)

e)

COOH

COOH

COOH

FCH2 COOH

2.57

4.14

COOH

OMe
OMe

4.17

COOH

g)

4.76
b)

f)

3.27

4.47

4.09

2.9. What is the function of TiCl4, when it acts as a catalyst in alkylations of silyl enol ethers
with alkyl halides?
2.10. Which is more basic of the hydroxide (OH -) and hydroperoxide (HOO -) anions, and
which is more nucleophilic? Why?
2.11. Which would you expect to give the greater proportion of O-alkylation on reaction with
the sodium salt of ethyl acetoacetate, propyl iodide, or propyl bromide? Why?

Part 3:

Hammett Relationships

Hammett constants for different substituent are given in the Table on the last page.
3.1

Relate the substituent constant values of table:Hammett constants, to the electrondonating or -withdrawing character of each substituent. How does this compare with
qualitative predictions of substituent effects on acidity? Why might you expect m and
p values for the same substituent to be different

3.2

Match the values with the appropriate reactions. Explain your reasoning.
Reaction constants: +2.45, +0.75, -2.39, -7.29.
Reactions:
a)
nitration of substituted benzenes
b)
ionization of substituted benzenthiols
c)
ionization of substituted benzenephosphonic acids
d)
reaction of substituted N,N-dimethylanilines with methyl iodide.

3.3. Determine the value of for the reaction shown from the data given:
Y
O

SO2

CH2 SO3 -

+ OH -

k (M-1s-1)

Y
H
CH3 O
CH3
Br
NO2

OH

37,4
21,3
24,0
95,1
1430

JACS 92,860(1970)

3.4
The basicity of a series of substituted benzyldimethylamines has been measured.
Determine whether these basicity data are correlated by the Hammet equation.
What is the value of ? What interpretation do you put on its sign?
X

CH2 N (CH3 )2

X
pKa

p-CH3O p-CH3
9,32
9,22

CH2 N (CH3 )2

p-F

8,94

9,03

m-NO2
8,19

+ H+

p-NO2
8,14

p-Cl

m-Cl

8,83

8,67

JACS 89,1158(1967)

3.5

Under strongly alkaline conditions (methoxide ion) HCl is eliminated from

2-chloro-2-methyl-1-phenylpropane to give 2-methyl-1-phenylprop-1-ene.

PhCH2 CMe2 Cl

PhCH=CMe2 +

HCl

From the following results for the effect of substituents in the phenyl ring on the rate
of the reaction, determine the Hammett value for this reaction.
Substituent
Relative rate (k/k0)

m-Cl
2.23

m-F
2.21

m-Me
1.77

m-t-Bu H
1.38 1.00

m-Me
0.77

p-MeO
0.60

3.6

The following partial rate factors(kf) were obtained for the bromination of monosubstituated benzenes hy hypobromous acid in 50 % aqueous dioxan containing
perchloric acid.
Substituent
kf

p-Me
58.9

p-t-Bu m-Me
38.9
2.51

m-t-Bu H
2.57
1.00

p-Cl
0.22

p- Br
0.15

Show that the values of kf fit a Hammet equation using + values and determine the
value of . Predict the kf value for p-fluorobenzene.
Do these results allow you to distinguish between H2+OBr and Br + as the brominated
spieces?
3.7*

The mechanism of semicarbazone formation from benzaldehyde involves

condensation, followed by elimination of water:
PhCHO + NH2NHCONH2
OH
PhCH NHNHCONH2

OH
PhCH NHNHCONH2

k1
k -1
k2

PhCH NNHCONH2 + H2O

The second step ( k2) is acid-catalysed. The effect of substituents in the benzene ring
of benzaldehyde upon the rate of reaction depends upon the pH, as shown by the
following figures.
Substituent
Relative rate

pH
p-OMe p-Me
H
p-Cl m- NO2 p- NO2
1.75
0.52
0.54
1.00
1.14
3.36
4.93
7.00
0.81
0.90
1.00
1.15
1.21
1.53
Continued next page
Calculate the Hammett value at both pH's and explain the difference in terms of a
change in the rate determining step.
3.8* The reaction between ethyl chloroformate and aniline is a two-step process, involving
addition followed by elimation.
O
EtO C Cl +

NH2

OH
NH C OEt
Cl

k1
k-1

k2

NH C OEt

The following kinetic data were obtained for the effect of substituents in the aniline on
the rate of reaction:
Substituent

p-OMe

103kobs 1mol-1sec-1 1209

p-Me m-Me
286

66.5

H p-Br
42.

5.57
4

m- Cl p-CO2 Et m- NO2 p- NO2

5.25

1.53

1.92

0.13

What may be deduced about the rate determining step in this reaction from the plot
of log kobs against -.
Suggest an experimental check on the proposed mechanism.
7

3.9*

In the presence of a base (potassiun t-butoxide in t-butanol) 2-phenyl-ethylbenzene

sulphonate undergoes elimination to give styrene and the mechanism of the reaction
is E2.
A

"

CH2

CH2 OSO2

CH

+ HOSO2

CH2

A kinetic study of the effect of substituents in ring B, with same substituent in ring
A, on the rate of reaction gives a good Hammett plot with slope of . Values of
have been determined as a function of the substituent in ring A, with following
results.
Substituent in ring A
Hammet value

p-MeO
1.24

p-Me
1.24

H
1.08

m-MeO
1.06

p-Cl
1.01

m-Cl
0.94

(A more positive value indicates greater accumulation of negative charge.)

How does the trend in the values of reflect changes in the transtion state with
different substituents in ring A?
3.10. Arrange the following substituted benzoate esters in order of their rate of hydrolysis
under basic conditions. Does this correlate to the substituent values used for Hammett
plots?
O

O
OMe

OMe

OMe
O2 N

Me
a

OMe

NO2
O

MeO

4.1

O
OMe

Part 4:

MeO

Orbital Symmetry reactions

Predict which of following compounds are classified as aromatic, or nonaromatic,

based on the Hckel rule.
a)

b)

d)

c)

e)

f)

CH3

g)

h)
H2C

CH3

CH2

4.2

Carry out an orbital symmetry analysis to determine if the each of the following
thermal transformations is allowed or forbidden.

b)

+ CH2 =CH2

a)
C6H5

N3

C6H5

+ HC CCO2CH3

N
N
CO2CH3

4.3

Although pericyclic reactions are, in principle, reversible, the oxy-Cope rearrangement

of 4-methyl-1,5-hexadiene-3-ol is irreversible. Account for this experimental
observation.

!
HO

4.4

Which of the following reactions are allowed according to the orbital symmetry
conservation rules? Explain.
H

(a)

H CO2 CH3

CO2 CH3

(b)

CO2 CH3

CH3 CO2

Just. Lieb.Ann.Chem. 615, 14(1958)

=
JACS 74, 4867(1952)

(c)

- N2

N2

JACS 82, 1972(1960)

(d)

Tetrahedron Lett. 839 (1976)

(e)

S
+

(CN)2 C

C(CN)2

4.5 a)

S CN
CN
CN
CN

Tetrahedron Lett.
2011 (1976)

Offer a mechanistic explanation of the following observations.

(a)

Optically active A racemizes on heating at 50C with a half-life of 24h.

H

A:
H

J.Org.Chem 33(4258)1968

4.5

b) On being heated at 320-340C, compound B produces 1,4-dimethoxynaphthalene

and 1-acetoxybutadiene.
CH3CO2

OCH3
OCH3

B:

OCH3

OCH3

4.6

CH3CO2 CH CH CH

CH2

JACS 100(637)1978

Is the following reaction thermally or photochemically allowed?

O
O

4.7

Suggest a mechanism by which each transformation could occur. More than one step is
involved in each case.
(a)

OCH3
CCH2 Br

H2 C

Ag O2 CCF3
Na2 CO3

H
H2 O

O
JACS 95, 1338(1973)

(b)

150o C
JACS 93, 1292(1971)

OH

(c)

100o C

CH3 CH

370o C

(d)

Tetrahedron Lett. 3387(1974)

JACS 99, 292(1977)

Give the structure, including stereochemistry, of the products expected for the following
reactions.

a)
b)

CH3

CH3

4.8

CCH

Ph2 C

JACS 96,2270(1974)

KH, THF
20 h, 25 oC

OH

JACS 97,4765(1975)

CH CH2

c)

PhCH2 CHSCH

CH2

H2 O
DME, reflux, 12 h

CH CH2

10

(C1 1H1 4O)

JACS 95,2693(1973)

d)

CH3 CO2 C

e)

4.9

JACS 96,4673(1974)

CCO2 CH3

JACS 95,2381(1973)

Suggest mechanisms for the following reactions. Classify the orbital

symmetrycontrolled process as clearly as you can with respect to type.
a)

HO

Tetrahedron 5,70(1959)

H OH

b)

AcOH

H3C

H 3C
H3C

CH3

Tetrahedron 24,6029(1968)

CH3

AcO

c)

CO2CH3

CO2CH3

CH3CO2

Tetrahedron Lett.3719(1969)

CO2CH3

4.10 Classify the following reactions as electrocyclizations, sigmatropic rearrangements,

cycloadditions, etc., and give the correct symbolism for the electrons involved in each
concerted process. Some of the reactions proceed by two sequential processes.
H3 C

a)

CH3

H O
H
O

JACS 97,10848 (1975)

SPh

b)

OCH3

c)

H H

O
OCH3

CH2OH
H

H H

SPh

H
HOCH2

< 25 oC

H
H

d)

CH3

JACS 98,5017 (1976)

CH2OH
CH2OH
JACS 104,5555 (1982)

CH3

CH2

CH2
CH2

JACS 100,654 (1978)

11

4.11 When 14C-labelled allyl 2,6-dimethyl ether undergoes para Claisen rearrangement, the
carbon atom originally attached to oxygen becomes attached to the aromatic ring.
Suggest a mechanism to account for that result.
OH
O
H3C

H3C

CH3

CH3

4.12 Will the thermal and photochemical closures of a cis,cis,cis,trans-decatraene by

conrotatory or disrotatory?
CH3
H
CH3
H

CH3
H
CH3
H

4.13 The conservation of orbital symmetry suggest that [1,3] superficial shifts are symmetry
forbidden while [1,5] shifts are allowed. Show how a consideration of the products of
the thermal rearrangement of 7,8-dideuteriocycloocta-1,3,5-triene might prove this
prediction.
H
D
H
D

4.14 Why does the triene 1 not readily isomertize to toluene?

CH3

CH2
(1)

4.15* At 170 1-mesityl-3-methylallene (1) isomerizes to a mixture of 2,5,7-trimethyl-1,2dihydronaphthalene (2) and cis-1-mesitylbuta-1,3-diene (3) in a two-step process.
H

CH3
CH3

CH3

(2)

CH3
CH3

CH C CH CH3
CH3

CH3

CH3
CH

(1)
CH
CH3

CH2

CH
(3)

Suggest a mechanism for these reactions and describe the processes in terms of the
conservation of orbital symmetry.

12

4.16 Arrange the following pairs of reagents in order of their rate of reaction with each other.
What will be the products of these reactions?
O
+

+
a

MeO

+
c

CO2 Me
+

O
CO2 Me

4.17 Draw a molecular orbital diagram for hexatriene (draw -orbitals only, and do not
worry about the relative sizes of the coefficients of the orbitals). Which is the HOMO
and which is the LUMO?
4.18. What is the product of the reaction between the olefin shown below and phenyl azide?

Part 5:

Problems related to Nucleophilic Substitutions

5.1

Explain the observation that the rate of the SN1 reaction of many RX derivatives is
retarded by the addition of X-.

5.2

The rate of formation of tert-butyl ethyl ether from the reaction of 2-bromo-2methylpropane (tert-butyl bromide) with ethanol does not increase if the better
nuleophile sodium ethoxide is added. Explain this observation.
-

(CH3 )3 CO C2 H5

(CH3 )3 CBr + (C2 H5 OH or C2 H5 O Na )

5.3

Suggest an explanation for the following results:

(CH3 )3 COH + NaCl

(CH3 )3 COH + NaCl

H2 O

no reaction

H2 O / HCl

(CH3 )3 CCl

5.4

Account for the observation that 1-bromo-1-phenylethane reacts with methanol to give
product with 27 percent inversion, while reaction with sodium methoxide produces 100
percent inverted product.

5.5

The rate of reaction is the same when tert-butyl alcohol reacts with either HCl or HBr.
However, if an equimolar mixture of HCl and HBr is used, tert-butyl bromide is the
major product and tert-butyl chloride is the minor product . Explain these results.

13

5.6.

Provide an explanation for each of the following experimental observations.

a) The optical rotation of a solution of (+)-2-phenyl-2-pentanol goes to 0o when the
compound is boils in formic acid.
b) The optical rotation of a solution of sodium bromide and (+)-2-bromopentane in
acetone also goes slowly to 0o. The explanation is different from that of part a).
c) When (R)-1-phenyl-1-bromobutane is allowed to react in boiling acetic acid, the
configuration of the acetone product is different from that obtained when the
reaction is carried out in acetone with sodium acetate.
d) Azid (N3-) is a weaker base than amide (NH2-).
e) The bicyclic compound 1-bromo[2,2,2]bicyclooctane does not hydrolyse under SN1
or SN2 condition.
f) The trans isomer of 2-chlorocyklohexanol is converted to cyclohexene oxide by
base, but the cis isomer is not:
O

Br
1-Bromo[2,2,2]bicyclooctane

Cyclohexen oxide

5.7

The rate of reaction of 2-halo-2-methylbutanes in aqueous methanol is different for

halogen = Br, Cl, or I. However each substrate gives the same mixture of 2-methoxy2-methylbutane and 2-methyl-2-butanol.
a) Explain these experimental results and write the appropriate chemical equations.
b) Predict the order of the haloalkane reactivities.

5.8

Solvolysis of A in aqueous ethanol proceeds about 600 times faster than the
comparable reaction of tert-butyl bromide. Consider steric factors to explain this rate
of enhancement.
CH3
[(CH3 )3 CCH2 ] C Cl
Compound A
2

5.9

Account for the observation that the slow rate of hydrolysis of a primary chloroalkane
can be markedly increased by adding a small amount of potassium iodide.

CH3 CH2 CH2 Cl + H2 O

but
CH3 CH2 CH2 Cl + H2 O

5.10

KI

CH3 CH2 CH2 OH

slow

CH3 CH2 CH2 OH

fast

Account for the observation that 1,1-dimethyl rather than the 1,2-dimethyl product is
favoured when hydrazine is alkylated with iodomethane.
Na2 CO3
H2 NNH2
+
2 CH3 I
H2 NN(CH3 )2
Hydrazine

1,1-Dimethylhydrazine

Iodomethane

14

5.11

Suggest a mechanism for the following reaction:

Cl
(CH3CH2) 2NCH2CH CH2CH3 + H2O

CH2OH

NaOH
H2O

(CH3CH2) 2NCH CH2CH3

5.12

Why would you expect the substitution by cyanide to be considerably faster in

DMSO (dimethylsulfoxide) than in ethanol ?

5.13

What is the effect on the rate of the following reactions from an increase in a solvent
dielectric constant ().
CH3

a)

b)

CH3

N CH
CH2
3
CH3

+
+

CH3O2C - C

S CH2

H3C

C - CO2CH3

N
CH3

CO2CH3

CO2CH3

5.14 In most instances hydrolysis of an alkyl halide is catalysed by hydroxide ion. However,
the rate of hydrolysis of t-butyl chloride in aqueous ethanol is almost unaffected by
addition of potassium hydroxide. Suggest a reason for this and explain why this effect is
observed with a t-butyl compound.
5.15 Hydrolysis of dimethylene chlorohydrin is a simple SN2 reaction.

ClCH2 CH2 OH + H2 O

HOCH2 CH2 OH + HCl

The rate of reaction is determined by following the appenrance of chloride ion.

A series of chlorohydrins [CI(CH2)nOH] were studied and the rate of reaction was
found to depend markedly upon the value of n.
n
2
3
4
5
1,82
7,79
1710
70
105 k min-1
With n = 4 and 5 tetrahydrofuran and tetrahydropyran were detected as the products of
reaction. Explain these observations.
5.19

Isotopic substitution of iodine in (+)-2-iodooctane by reaction with iodide ion causes

racemization. Explain why racemization is complete when half the iodine has
exchanged. Iodine exchange was followed by the use of a radioactive isotope.

5.17 What would you expect would be the product of the reaction between the ,unsaturated carbonyl compound below and a thiol?
O

15

5.18 Enolates are often made by treatment of the carbonyl compound with LDA, itself
prepared from diisopropylamine and butyllithium. Why is butyllithium not used directly
to form the enolate?
5.19 Ethyl bromide and ethanol can be interconverted by hydrolysis of ethyl bromide and
reaction of ethanol with bromide ion. For each direction, should the reaction be run in
acid or base, and why?
5.20 In aliphatic nucleophilic substitution reactions, fluoride is the most difficult of the
halides to displace. However, in aromatic nucleophilic substitutions, it is the easiest to
displace. Why?

Part 6:
6.1

Problems related to Elimination reactions

Provide an explanation for the different product mixtures obtained when 3-methyl-2bromobutane is treated with chloride or acetate in acetone.
Cl

Cl- / acetone
Br
(CH3)2CH CH CH3

50 %

(CH3)2C CH CH3

50 %

(CH3)2CH CH CH3

(CH3)2CH CH CH2
OAc

AcO -/ acetone

89 %

6.2.

11 %

(CH3)2CH CH CH3

Account for the change in ratio of 1-alkene to 2-alkene product as the base changed in
the dehydrobromination of 2-bromo-2,3-dimethylbutane.
Base =
1-ene / 2-ene =

C2H5O-

0.25

(CH3) 2CO-

CH3CH2C(CH3) 2O-

(CH3CH2) 3CO-

4.3

2.7

11.4

6.3

When the elimination of HF from 1,1-dichloro-2,2,2-trifluoroethane is carried out with

sodium methoxide in deuterated methanol, 1,1-dichloro-1-deuterio-2,2,2trifluoroethane can be recovered from the reaction mixture. How does this result fit
into the E1cB mechanism proposed for the elimination reaction ?

6.4

Elimination of HCl from A gives kinetic data consistent with an E1cB mechanism.
Explain why the unusual E1cB process might be expected in this example.
Compound A

O
Cl
p-ClC6H4C CH CHC6H4Cl-p
Cl

16

6.5

Account for the following change in the ratio of the 1-pentene to 2-pentene products as
the leaving groups changes
X
CH3 CH2 CH2

NaOEt
EtOH

CH CH3

X=
1-ene / 2-ene =

- Br
0.45

CH2 + CH3 CH2 CH

CH3 CH2 CH2 CH

- OTs
0.97

- S+(CH3) 2
6.7

CH

CH3

- N+(CH3) 3
! 50

- SO2CH3
7.7

6.6

Explain the observation that cis-2-phenylcyclohexyl tosylate undergoes elimination of

tosylic acid (TsOH) about 104 times faster than the trans isomer.

6.7

Propose an mechanism for the formation of meso-1,2-dibromo-1,2-diphenylethane by

the addition of bromine to Z-stillbene in nitromethane.

6.8

Account for the observation that elimination of HCl is more rapid from A than B.
Cl
H

6.9

Cl
H
Cl

Cl

H
H

Hydrogen chloride is eliminated from DDT (1,1,1-trichloror-2,2-di-pchlorpohenylethane) by the action of ethoxide ion in alcoholic solution.

Cl
2

CH CCl3

Cl

C
2

CCl2

HCl

Do the following observations indicate an E1, E2, or E1cB mechanism?

a) The rate of reactions is first order in both DDT and ethoxide ion.
b) Introduction of deuterium at the 2-position reduces the rate by a factor of 3.8.
c) Using tritiated ethanol (EtOT) as solvent does not introduce tritium into unreacted
DDT.
6.10 The elimination reaction shown below gives predominantly the terminal olefin. Is this
reaction under kinetic or thermodynamic control? Why?
i-PrONa
Et

Br

Et

6.11. Which of these bromoalkenes will give an alkyne and which will give an allene on
elimination with base?
Br

Br

17

6.12 Which of the following compounds would you expect to give a greater ratio of
elimination to substitution on treatment with sodium ethoxide? What would the effect
on these ratios be of using potassium t-butoxide instead of sodium ethoxide?
O

Br

Br

Part 7:

Problems related to Addition reactions

7.1

Although an aryl group is usually found to be electron-withdrawing relative to alkyl,

aromatic aldehydes tend to be less reactive than aliphatic aldehydes.
Use the concepts of resonance to account for the result.

7.2

Heats of formation of isomeric aldehydes and ketones indicate that ketones are
typically 5-10 kcal/mol (20-40 kJ/mol) more stable than aldehydes. Refer to the
resonance structures for 2-propanone (acetone) and propanal as a basis for
rationalizing this general observation.

7.3

Addition of methyl magnesium bromide to 2-methylcyclohexanone followed by

iodine-catalysed dehydration of the resulting alcohol gave three alkenes in the ratio
A : B : C = 3 : 31 : 66. Each isomer gave a mixture of cis- and trans-1,2-dimethylcyclohexane on catalytical hydrogenation. When the alkene mixture is heated with a
small amount of sulfuric acid, the ratio A : B : C is changed to 0 : 15 : 85. Assign
the structures to A, B, and C. J.Org.Chem, 38(316)1973

7.4

The acid-catalysed hydrolysis of 4-methoxybut-3-en-2-one (1) is associated with an

entropy of activation of 26 e.u.
O
MeO

CH CH
(1)

H+

C CH3

+ H2 O

HC CH

OH
C CH3

+ MeOH

Suggest a mechanism of reaction, indicating the rate-determining step.

7.5

Acetone reacts with hydroxylamine to give an addition compound which then

undergoes slow, acid-catalysed dehydration to form an oxime.

H3 C

H3 C
C

O + NH2 OH

H3 C

k obs

OH
C NHOH

H3 C
H3 C
C
H3 C

NOH

+ H2 O

1,5

1,0

0,5

pH
2
4
6
Figure 4. Variation of rate of reaction with pH for
the reaction of acetone and hydroxylamine

The variation of rate of reaction with pH is shown on the graph in Figure 4.

Explain the shape of this curve.
18

7.6

7.7

Comment on the observation that S the hydrolysis of t-butyl trifluoroacetate is

+ 14.8 e.u. and that for methyl trifluoroacetate is - 32.3 e.u.
1,2-Diphenyl 1-propanol may be prepared in either of two ways:
a)
lithium aluminum hydride reduction of 1,2-diphenyl-1-propanone.
b)
reaction of 2-phenylpropanal with phenylmagnesium bromide.
Which method would you choose to prepare the threo isomer? Explain.
JACS 74(5828)1952

7.8

Optically active threo- and erythro- 3-phenyl-2-butyl tosylate were each allowed to
solvolyze in acetic acid until about 60 percent had been converted to product.
Chemically unchanged starting material was then recovered, and it was found that the
threo-tosylate was 94 % racemized but the erythro-tosylate was still optically pure.
Show how these support the phenonium ion intermediate.

H
H3C

H
CH3

H
CH3
OTs

H
H3C

HOAc

C
H
CH3

H
H3C
H
H3C

C
OAc

+
C

OAc

H
CH3

threo-3-Phenyl-2-butyl acetate

7.9

Show how water labelled with oxygen 18 can be used to verify alkyl oxygen cleavage
in acid-catalysed hydrolysis of tert-butyl acetate.
Tert-butyl acetate

O
CH3C O C(CH3) 3

7.10 Arrange the following carbonyl compounds in order of their reactivity towards
nucleophiles.

7.11 When propene is treated with bromide in the presence of chloride ions, a mixed halide is
formed. What is its structure, and why does this particular compound form?

19

Part 8:

Miscellaneous problems

8.1

Many examples of bromination of activated aromatic compounds (i.e., anisole or

acetanilide) in acetic acid follow third-order kinetics.
Rate = K3[Ar][Br2]2
Suggest a mechanism consistent with this kinetic expression.

8.2

Suggest a reason for the greater stability of - over naphtalenesulfonic acid.

SO3 H
+

8.3

H2 SO4

! 80 o C

SO3 H

! 160 o C

Hydrolysis of phthalamic acid (1) to phthalic acid (2) was thought to involve
elimination of ammonia and intermediate formation of phthalic anhyride.
O
C

CONH2

COOH

H2 O

C
O

COOH

COOH

(2)
(1)
This possibility was investigated by an analysis of the products of reaction between
13
phthalamic acid labelled with C in the amide group and water enriched with 18O.
Show how this could demonstrate the intermediacy of phthalic anhydride and suggest
how the products might be analysed.
8.4

For the following pairs of reactions, ondicate which you would expect to be more
favorable and explain the basis of your prediction.
a)

Which isomer will be converted to a quaternary salt more rapidly?

JACS 36(1688)1971

N(CH3 )2

or

(CH3 )3 C

b)

Which compound will undergo hydrolysis more rapidly?

O
CH3
O

c)

N(CH3 )2

(CH3 )3 C

JACS 104(4706)1982

or

NO2

NO2

Which compound will be more rapidly oxidized by chromic acid?

JACS 98(8407)1976

HO

or
HO

20

8.5

The reaction between water and -butyrolactone is pH independent and must involve
attack by an undissociated water molecule on the lactone. Hydrolysis by water
18
18
containing O results in an acid containing O in the -hydroxy group.
CH3

1 8OH

CH CH
O

+ H2 1 8O

CH3 CH CH2 COOH

Also, (+)-butyrolactone hydrolyses to (+)--hydroxybutyrie acid. Compare the

configurations of the (+)-lactone and (+)-acid.
8.6

a) Account or the enhanced acidity of the methyl hydrogen atoms in 4-methylpyridine

but not in 3-methylpyridine.
b) Why does A decarboxylate much more readily the B does?
50 o C

200 o C

CH2 CO2 H

CH3

CO2 H

8.7

Ethyl vinyl ether is readily hydrolysed in dilute acid.

EtO

CH

CH2

H2 O

H+

EtOH + CH3 CHO

Suggest a mechanism consistent with the following observations, paying particular

attention to the position of protonation.
a) The reaction is subject to general acid-catalysis.
b) The reaction is faster in H2O than in D2O by a factor of 2.93.
18
c) The ethanol obtained by hydrolysis in isotopically labelled water contains no O.
d) If hydrolysis occurs in D2O only one deuterium appears in the acetaldehyde.
8.8* Hydrolysis of -acetoxy-p-nitrostyrene is acid-catalysed.
O

O COCH3
O2N

C
CH2

O2N

+ H2 O

CH3 + CH3 COOH

In 6 % sulphuric acid there is a kinetic isotope effect k(H2O)/k(D2O) of 0.75 but in 69 %

sulphuric acid the size of this effect changed to 3.25.
What may be deduced about the mechanism of hydrolysis from this change?
8.9

In the presence of acetate ion, nitromethane reacts readily with bromine to give,
initially, monobromonitromethane.

CH3 NO2 + Br2

CH2 BrNO2 + HBr
The fully deuteriated compound (CD3NO2) reacts 6.6 times more slowly than the
isotopically normal compound.
What is the rate-determining step in this reaction?

21

8.10* Substituted methyl benzoates hydrolyse rapidly in 95 % sulphuric acid. A study of the
effect of substituents in the phenyl ring on the rate of reactions gave the following
results.
Substituent

p-Me

m-Me

m-Cl

m-Br

104 k sec-1

2,41

1,51

0,65

0,035

0,032

Determine the value of p for this reaction and predict the rate constant for the hydrolysis
of methyl p-fluorobenzoate.
For the hydrolysis of methyl o-methylbenzoate and methyl p-methoxybenzoate the rate
-4
-1
-4
-1
constants are 182 x 10 scc and 10.2 x 10 scc , respectively.
Comment on these results.
Substituents have very little effect upon the rate of hydrolysis of methyl benzoates in
dilute sulphuric acid. Compare hits observations with the results given above and
suggest an explanation. (Values of can be found in the Table on the last page))
8.11* Comparisation of the gas phase acidity of benzonic acids with pKa values of the same
compounds in aqueous solution provides some interesting relationships.
a ) The trend in acidity as a function of substituents is the same but the magnitude of the
substituent effect is much larger in the gas phase. (The G for any given
substituent is about ten times larger in the gas phase.)
b ) Whereas acetic acid and benzonic acid are of comparable acidity in water, benzonic
acid is much more acidic in gas phase.
c ) While the substituent effect in the gas phase is assumed to be nearly entirely an
enthalpy effect, it can be shown that in solution the substituent effects is largely the
results of changes in S.
Discuss how the change from gas phase to water solution can cause each of these
effects.
JACS 94, 2222(1977)
8.12* The rates of hydrolysis of the three related esters have been studied as a function of pH,
with results shown in Figure 7.
The entropy of activation for the hydrolysis of 1 is -41.0 e.u.

(1)

O
O C OEt

O
O C OEt

OH

OCH3
(2)

O
O C OEt
HO
(3)

See next page

22

Lg kobs
-30

- 40

(3)
(1)

(2)

pH
11
10
12
Figure 7. Plot of the rate of hydrolysis of the three esters versus pH.

Suggest mechanisms for these reactions.

8.13 Predict whether normal or inverse isotope effects will be observed for each reaction
below. Explain. Indicate any reactions in which you would expect kH/kD > 2.
The isotopically substituted hydrogens are marked with asterisks.

(a)

CH3 CH2 *CH CH2 *CH3

OSO2 Ar

EtOH
H2 O

CH3 CH2 *CH CH2 *CH3

CH3 CH2 *CH CH2 *CH3

OH

JACS 92, 3191(1970)

CH3 CH2 *CH CH2 *CH3

OEt

(b) Ph2 C C O +

PhCH CH2 *

PhC

JACS 91, 3106(1969)

H C

PhC

CH2 *

H C

CH3 CH2 C

OC2 H5

H+

H OC2 H5

fast

CH3 CH2 CH* OC2 H5

+ H2 O

fast

slow

CH2 *

CH3 CH2 C

OC2 H5

H*
O + HOC2 H5

CH3 CH2 C

H*

Ph

Ph

(c) CH3 CH2 CH* (OC2 H5 )2

H*

JACS 93, 3002(1971)

8.14* Keto acids are fairly readily iodinated by molecular iodine and the mechanism appears
to be the same as that for acetone

CH3 COCH2 (CH2 )nCOOH + I2

CH3 COCHI(CH2 )nCOOH + HI

The rate of reaction in the absence of a catalyst has been studied as a function of n, with
the following results.
a ) Iodination of the anion:
n
108 k sec-1

1
29,8

23

2
179

3
72

4
3,4

5
3,2

8.14* b ) Iodination of the ethyl ester:

n
108 k sec-1

1
0,20

2
0,32

What do these results indicate?

8.15. Which of the following molecules will react with phenyl magnesium bromide, and what
will the products be?

8.16 Treatment of benzene with sodium in liquid ammonia in the presence of an alcohol
produces 1,4-cyclohexadiene; this is known as Birch reduction. Treatment of anisole
gives 1-methoxy-1 ,4-cyclohexadiene, not 3-methoxy1,4-cyclohexadiene. Why?
8.17 A reaction between methylene and cis-2-butene gave trans-1,2-dimethylcyclopropane.
What does this tell us about the electronic configuration of the carbene in this reaction?
8.18 The first mixture of two carbonyl compounds shown below gives a mixture of four
compounds when treated with base, but the second mixture gives a single product under
the same conditions. Explain.
O

O
+

H
O

H +

Base

Four products

Base

One product

O 2N

8.19 Reaction of the ketone shown below with hydroxylamine gives an oxime, A, that
rearranges on treatment with acid to give a further product, B, hydrolysis of which gives
the carboxylic acid and the amine shown. What are the intermediates, A and B, and
what is the geometry of the oxime?
O
NH2OH

H+

H+/H2O

NH2

O
+
HO

8.20 Sulphides are readily oxidized to sulphoxides on treatment with hydrogen peroxide.
Write a mechanism for this transformation under acidic conditions. Sulphoxides can, in
turn, be oxidized to sulphones. The mechanism of this reaction is the same as the
oxidation of sulphides in neutral or acidic conditions, but in base a different mechanism
operates. Suggest a likely mechanism.

24

8.21 But-2-ene can be converted to 2-bromobut-2-ene by the following two transformations.

What is the structure of the intermediate? Draw mechanisms for these steps and explain
the stereochemistry.
Br2

Br

Base

Intermediate

8.22*When the amino acid threonine is treated with nitrous acid in the presence of chloride
ions, two isomeric products are formed in addition to the expected product. What is the
mechanism of their formation, and what would you expect their stereochemistry to be?
OH

OH
OH

HONO
Cl -

OH

NH2

+ 2 other products

Cl

8.23 a)We know that it is generally the acyl-oxygen bond that is cleaved in ester hydrolysis
rather than the alkyl-oxygen bond. One of the main pieces of experimental evidence for
this came from an experiment that used 180. How might such an experiment be carried
out? What result would you expect, and how would this be different if the alkyl-oxygen
bond were cleaved?
b) When the alkyl group of an ester is tertiary, hydrolysis under acidic conditions takes
place with alkyl-oxygen cleavage. Could this be distinguished from the above
mechanism kinetically? Apart from 180 labelling, what other evidence might be used to
verify this mechanism?
8.24. Treatment of methyl -bromopropionate with hydrazine gives a mixture of products as
shown below. A possible mechanism for the reduction is that the hydrazine function is
somehow oxidized to an azo function, which then undergoes an elimination reaction to
give the enolate, and hence the reduced product. Suggest a way of discovering whether
this mechanism is possible.
O

NH2 NH2

OMe

NHNH2

Br

NHNH2

NHNH2
O

O
NHNH2

[O]

O
NHNH2

NHNH2

NHNH2

N
N

Base

8.25 When acetone is brominated, the rate of reaction is independent of the concentration of
bromine. Deuteriated acetone is brominated mote slowly than normal acetone. What do
these facts tell us about the mechanism of there action?

25

TABLE

Hammett Relationship

Required values for exercises of the constants are given in the following table. The most
complete collection is that of D.H. McDaniel and H.C. Brown
(J.Org.Chem, 23, 420 (1958).
Table
Substituent
p-MeO
m-MeO
p-Me
m-Me
p-But
m-But
p-F
m-F
p-Br
m-Br
p-Cl
m-Cl
p-CO2Et
p-NO2
m-NO2

- 0,27
0,12
- 0,17
- 0,07
- 0,20
- 0,10
0,06
0,34
0,23
0,39
0,23
0,37
0,45
0,78
0,71

26

Hammett constants
+
- 0,78
0,05
- 0,31
- 0,07
- 0,26
- 0,06
0,07
0,35
0,15
0,41
0,11
0,40
0,48
0,79
0,67

- 0,27
- 0,17
- 0,07

0,22
0,38
0,68
1,27
0,70