2nd YEAR
ORGANIC CHEMISTRY TUTORIAL SHEET
Physical Organic Chemistry
Reading:
Lecture notes – Physical Organic Chemistry
Clayden, Greaves & Warren Edition 2 Chapters 12, & 39
Modern Physical Organic Chemistry by Anslyn and Dougherty
Advanced Organic Chemistry, Part A, 5th Edition by Carey and Sundberg
Topics for notes:
You need to be familiar with the following concepts which are useful in the determination of
reaction mechanisms and will have been covered in lectures:
Energy diagrams; Rate Determining Step; simple kinetic expressions; the Hammond Postulate;
Curtin-Hammett principle; principle of microscopic reversibility; kinetic and thermodynamic control;
isotopic labeling; kinetic isotope effects; tautomerism and conformational equilibrium; solvent
effects; simple linear free energy relationships; the Hammett equation; non-linear Hammett plots;
specific and general acid, base and nucleophilic catalysis.
Tutorial Problems
1) Conformers A and B of the amine C are in rapid equilibrium. Explain why conformer B is more
stable than conformer A and why the diastereoselective alkylation of C gives the quaternary
ammonium salt D.
N
CH3
H 3C
CH3
N
N
H 313 C
13 CH
A
B
N
CH3 I
3I
D
C
2) The reaction below shows third order kinetics, suggest a mechanism.
O
O
NaOH
Ph
Ph
H 2O, EtOH
Ph
rate= k[ketone][HO -]2
Ph
OH
3) Write a rate law that would apply to the rate of product formation where the second step is ratedetermining and the first step is in equilibrium.
H
H
Br
Br
k1
+ R3N
k–1
H
Br
H
H
k2
+ R3NH
Br
Br
+ Br–
H
Br
H
N+R3
Br
Br + R3N
k3
4) Hydrolysis of the lactone below could potentially proceed by (at least) three different
mechanisms: i) BAC2 (i.e. standard tetrahedral mechanism), ii) via an SNAr reaction, iii) via
formation of an enolate followed by a ketene. Draw these three possible mechanisms. How would
a) deuterium labelling, b) 18O labelling, help to distinguish the mechanisms.
O2N
O
O
NaOH, water
O2N
O
O
OH
2nd YEAR
ORBITALS & MECHANISM II
5) Explain how both methyl groups in the product of this reaction come to be labelled. If the
starting material is reisolated, at 50% reaction, its methyl group is also labelled.
O
OMe
Cl
O
OMe
mixture of CH3 and CD3
Me
mixture of CH3 and CD3
CD3
Ag
6) Predict which of the two diastereomers of the carboxylic acids shown has the lower pKa in water.
CO2H
CO2H
tBu
tBu
7) In water, acetic acid is about three times more acidic than the pyridinium ion (C5H5N+H). In
MeOH, the relative acidities reverse. The pyridinium ion dissociates about the same amount in
both solvents, but acetic acid dissociates almost 10000 times less in MeOH. Explain the reversal.
8) What would be the effect of solvent changes on these reactions? Would the reactions be
accelerated or retarded by a change from a polar to a non-polar solvent?
Ph 3P
O
Br 2
Ph 3PBr
solvent
O
NMe 3
heat
solvent
O
CO2 + NMe 3
R
OMe
O
NH 3
solvent
R
NH 2
9) Explain why compound A is hydrolysed in base 8300 times faster than compound B, and
compound C is hydrolysed in acid 100000 times faster than compound D.
H
O
CO2Me
CO2Me
O
A
MeO
O
C
B
OMe
D
10) What do the measured kinetic isotope effects tell us about the mechanisms of the following
reactions?
Br
O
Ph
HO- / Br2
X
O
Ph
X = H,D; kH/kD = 6.1
O
Br
tBu
Y
S
O O
X
A: X = Y = H
B: X = H, Y = D
C: X = D, Y = H
OH
H2O, heat
tBu
Y
X
solvolysis rates:
kA/kB = 1.44
kA/kC = 1.10
-2-
2nd YEAR
ORBITALS & MECHANISM II
11) Suggest mechanistic interpretations for the following observations.
(a) Chromium trioxide oxidations of secondary alcohols are normally associated with a primary
isotope effect of about 7.0 for CHOH vs CDOH. The case below is an exception having a primary
isotope effect of 1.0.
Me Me
Me Me
H
H
Me
Me
H
AcO
CH2OAc
Me
CrO3, H+
AcOH
Me
H
AcO
H
H[D]
Me Me OH
Me
CH2OAc
Me
H
Me Me O
(b) The rate constant for the solvolysis of X=H, Y=H is 1.14 times greater than that of the dideutero
X=D, Y=H but almost identical (0.99) with that of the monodeutero X=H, Y=D.
X
Me
X
Cl
Y
12) The Hammett equation can be written as log10(kx/kH) = ρσx
(a) How is the substituent constant σx defined?
(b) Put the following substituents in order of increasing σx value and say whether each σx value is
positive or negative. Justify your answer.
Para-NO2, meta-CH3, para-NH2, para-CΞN, meta-OMe
(c) How is the Hammett reaction constant ρ defined? Explain why the Hammett equation is called a
linear free-energy relationship.
(d) Explain how Hammett reaction constant can be used to elucidate reaction mechanisms, using
the following reactions to illustrate your answer.
Cl
X
OEt
Ph + EtOH
X
Ph
+ HCl
ρ = –5.1
+ Cl–
ρ = –0.3
+ HBr
ρ = +4.9
OH
X
X
Cl
Br
NO2
+ HO–
X
X
+
N
H
Ph
N
NO2
(e) Why are ortho-substituents normally excluded from Hammett relationships?
(f) Discuss the possible causes for non-linear Hammett plots
-3-
2nd YEAR
ORBITALS & MECHANISM II
13) Interpret as fully as possible the following data concerning the reaction of PhCΞCH with Cl2.
(a) Phenyl acetylene reacts with chlorine in AcOH at 25 ºC according to the rate law:
-d[Cl2]/dt = k[Cl2][PhCΞCH]
(b) The Hammett reaction constant for this reaction ρ (obtained from a series of ArCΞCH) is –4.2,
correlating better with σ+ than σ. For comparison, the acid catalyzed hydration of ArCΞCH to
ArCOMe has a ρ value of –4.3, also correlating better with σ+ than σ.
(c) Four main products are obtained: two pairs of isomers formula C8H6Cl2 and C10H9ClO2. The
isomers of C10H9ClO2 both yield C8H7ClO on acidic aqueous work-up. On treatment with zinc and
AcOH, this compound is converted into C8H8O, which has a 1H NMR (CDCl3): δ 2.60 (s, 3H), 7.27.7 (m, 3H), 7.8-8.3 (m, 2H); and infra-red (film): υmax 1685 cm–1.
(d) The two isomers of formula C8H6Cl2 are produced in nearly equal amounts.
14) Between pH 2 and 7 the rate of hydrolysis of this ester is independent of pH. At pH 5 the rate is
proportional to the concentration of acetate ion in the buffer solution and the reaction goes twice as
fast in H2O as in D2O. Suggest a mechanism for the pH-independent hydrolysis. Above pH 7 the
rate increases with pH. What kind of change is this?
O
F 3C
O
NaOAc
H 2O
SEt
F 3C
OH
+ EtSH
15) What does the measured pH rate profile for hydrolysis of phenyl 2-aminobenzoate in water at
50 ºC (given below) tell us about the mechanism of hydrolysis at different pH ranges? Propose
relevant mechanisms.
O
O
NH 2
–3.0
–4.0
Log(K obs/S–1)
–5.0
3
4
5
6
7
8
pH
9
10
11
16) The following reaction may proceed by elimination followed by conjugate addition. What
experiments could you propose to support (or disprove) this mechanism?
O
Ph
O
NaCN
Cl
H 2O, EtOH
Ph
CN
-4-