III 2014 Paper2

NATURAL SCIENCES TRIPOS Part III
Monday 26th May 2014
9.00 to 12.10
CHEMISTRY: PAPER 2
Candidates should attempt FOUR questions, taken from at least THREE different sections.
Where a question is divided into sections, the approximate division of marks between
sections is indicated at the end of the question.
Linear graph paper is available if required.
A Periodic Table, the structures of the amino acids and nucleotide bases, the values of
physical constants, character tables and selected mathematical formulae will be found in
the data book provided.
Write on ONE side of the paper only.
The answers to each question should be returned separately.
A separate cover sheet for each question should be completed.
Calculator students are permitted to use an approved calculator.
STATIONERY REQUIREMENTS
Graph paper (2 sheets)
Lined paper
Rough work pad
SPECIAL REQUIREMENTS
Department of Chemistry Data Book
Question record card
You may not start to read the questions printed on

the subsequent pages of this question paper until
instructed that you may do so by the Invigilator.
During the first 10 minutes of the examination
you are permitted to read the paper, but you may
not start writing your answers until this time has
elapsed.
SECTION A
M2 Advanced Diffraction Methods
18
Answer all parts of the question.
(a) Electron diffraction is an extremely useful technique in the identification of unknown materials but nevertheless is a poor method of determining the exact atomic
structure. Bearing in mind the strength of the interaction of electrons with matter
compared to that of x-rays and neutrons, discuss briefly the validity of this statement.
(b) The low-temperature form of HfO2 can readily be prepared in microcrystalline form
using sol-gel methods, but crystals of a size large enough for single-crystal diffraction
studies cannot be grown without converting to the high-temperature phase. When
examined by electron diffraction, three principal reciprocal lattice patterns can be
obtained.
Pattern A shows an orthogonal arrangement of diffraction maxima, with spot separations measured as 2.471 and 2.410 mm; pattern B is also orthogonal, with spot
separations of 2.394 and 2.410 mm; and pattern C shows an oblique arrangement,
with spot separations of 2.471 and 2.394 mm, the angle between the rows of spots
being 80.8 .
If the camera length is 50 cm, and the patterns are recorded with 200 kV electrons
( = 0.0251 ), calculate the unit cell parameters of HfO2 . In labelling the axes, you
should use the convention that |a| is less than |c|.
(c) It is noted that in patterns A and B alternate spots along the axis with separation
2.410 mm are invariably very weak, and a similar effect is also observed in pattern C,
where alternate rows of spots with separation 2.471 mm are also systematically weak.
Explain this observation.
[Qu. 18 continued on next page]
[Continuation of Qu. 18]

(d) The x-ray powder diffraction pattern is complex but can be indexed once the unit cell
dimensions are known. When the line intensities are measured, these can then be
used to determine the structure. If CuK radiation ( = 1.5418 ) is used, two very
strong lines are noted at 2 = 34.21 and 35.34 . From the unit cell derived in (b),
show that these correspond to the (002) and (200) beams, respectively.
The measured absolute values of |F(002)| and |F(200)| (after correction for all experimental factors) are found to be 207 and 227. If there are four hafnium atoms in the
unit cell and the space group is assumed to be P21 /c these will occupy positions with
coordinates (x, y, z) and (x, 21 y, 12 + z).
Neglecting the oxygen atoms, derive an expression for the structure factors F(002) and
F(200), and hence find possible x- and z- coordinates for the hafnium atoms. At these
values of sin ()/ the scattering factor of hafnium is approximately 60 electrons.
(e) Once approximate hafnium atomic coordinates are known, how could you then refine
their values and how would you locate the oxygen atoms?
Approximate division of marks: (a) 20%, (b) 20%, (c) 10%, (d) 30%, (e) 20%.
[TURN OVER
19
(a) For a weak phase object (i.e. amplitude scattering can be neglected) show that the
image intensity from a periodic specimen with a centre of symmetry can be written
in the form:
X
II (r) = 1 4
V(Sn ) cos (2r.Sn ) sin ((Sn ))
+Sn
where is an interaction parameter, V(Sn ) are the Fourier coefficients of the projected
potential in the specimen, and sin ((Sn )) is the Phase Contrast Transfer Function,
(PCTF), given by:
!
o
2 n 1
1
2 2
4 4
sin ((Sn )) = sin
F
S
S
n
n
4 s
2
(b) As the expression derived in (a) indicates, the image contrast is seriously perturbed
by the PCTF, and direct interpretation in terms of atomic positions is frequently
not possible. Indicate how this problem may be solved by Fourier transformation
of the image intensity, and describe the two main problems which are commonly
encountered if this is attempted.
(c) An attempt is made to determine the structure of a zeolite membrane by high resolution electron microscopy. Because the specimen is extremely sensitive to electron
beam irradiation, it is necessary to carry out the examination in a liquid helium
cooled specimen holder, which, because of its bulk, necessitates a large pole-piece
gap and consequently a comparatively large spherical aberration coefficient. The
images therefore contain a considerable amount of detail but cannot be interpreted
directly in terms of any known zeolite structure.
In order to solve the problem, a series of three images is taken, with a constant focus
increment F between each. The power spectra of these images are then calculated,
and the weights of the peaks W(hkl) in these are noted. Assuming that these peak
weights are related directly to the Fourier coefficients V(S(hkl) ) by the relationship:

W(hkl) = V(S(hkl) ) sin (S(hkl) )
describe algebraically how you would actually deduce the defocus increment F and

hence the value of sin (S(hkl) ) for a given peak in the power spectrum, and thus
calculate the correct Fourier coefficient. You may assume that no allowance for
chromatic aberration is necessary.

(d) When this operation is performed on the zeolite images it is noted that some very
weak peaks are observed in the power spectrum at high S(hkl) values and these appear
to be completely unaffected by alteration of objective lens defocus. Suggest how
these weak peaks could arise, and why they are independent of focus position. Would
you expect them to contribute to the correct contrast of the image?
Approximate division of marks (a) 20%, (b) 20%, (c) 40%, (d) 20%.
[TURN OVER
SECTION B
M3 Magnetic Materials
20
(a) Three new magnetic materials F, G and H have been prepared by combining anionic complexes containing Fe3+ anions with cationic species containing various
manganese fragments. In all materials the iron and manganese are bridged by the
cyanide ligands which are part of the Fe-anionic complex.
O
N
N
N
Mn
Fe
N
N
A
N
N
N
D
N
Mn
O
E
Complex F is made by combination of anion A with cation B. Complex G has the

formula [A]4 [Mn(D)(MeOH)]2 and complex H has the formula [A]2 [Mn(C)2 ]; both
G and H contain Mn2+ . The connectivity of the metal ions in compounds F, G and H
is shown below.
Fe
Fe
Mn
Mn
Fe
Mn
Mn
Fe
Fe
Mn Fe Mn Fe Mn Fe
Fe Mn
Mn
Mn
Fe
Fe
connectivity in F
Mn
Fe
Fe
connectivity in G
connectivity in H

The magnetic susceptibilities of all three compounds are shown in the graphs below.
For all three compounds use the limiting high-temperature value of T to determine
the spin state of the ions.
F

[TURN OVER

(b) A further compound, I, which has formula [A][E] can be prepared which has a simple
alternating FeMn chain containing Mn3+ . Briefly explain how the BonnerFisher
approach could be used to model the magnetic susceptibility of I.
Use Kambe vector coupling to derive the magnetic energy levels in H.
(c) The susceptibility and magnetisation for I are shown below. Determine the type of
magnetic behaviour displayed by this compound. What other types of measurement
could be used to confirm this assignment?
Approximate division of marks: (a) 30%, (b) 40%, (c) 30%.
21
(a) A double perovskite Ca3 (Mn2 Nb)O9 (i.e. A3 BB0 2 O9 ) that contains two different ions
(Mn and Nb) on the B site of the perovskite structure has been synthesized and
investigated for its magnetoresistance and other electronic/magnetic properties. Some
magnetic properties of this material are compared with those of three simpler ABO3
perovskites below. (AFM = antiferromagnetism; TIP = temperature independent
paramagnetism)
CaMnO3
Weiss
constant (K)
472
magnetic
property
AFM
LaMnO3
+52
AFM
structure
CaVO3
Ca3 (Mn2 Nb)O9
Curie/Neel
meff per formula
temperature (K)
unit (B )
125
140
TIP
99
ferrimagnetic
0.14
40
8.8
Rationalize the Weiss constants, magnetic properties and CurieNeel temperatures

(T N ) of CaMnO3 and LaMnO3 , describing the dominant magnetic interactions that
give rise to these properties.
Explain briefly what you would observe on lowering the temperature below T N in the
neutron diffraction patterns of the two structures, commenting on any differences in
the magnetic unit cells of the two materials.
[TURN OVER
10

(b) The B(B0 )O6 octahedral units are tilted in Ca3 (Mn2 Nb)O9 , resulting in a monoclinic
space group P21 /n, with two different B sites and unit-cell parameters of a = 5.40 ,
b = 5.48 , c = 7.61 , = 90.25 . The atomic coordinates and site occupancies of
the cations are listed below.
atom
Wyckoff site
x/a
y/b
z/c
occ.
Ca
4e
0.986(2)
0.043(2)
0.247(3)
Mn
2d
0.5
0.65
Nb
2d
0.5
0.35
Mn
2c
0.5
0.5
0.68
Nb
2c
0.5
0.5
0.32
How many Ca and Mn ions are there per unit cell? Comment on the extent of cation
ordering of Mn and Nb over the two B sites of this perovskite structure.
Use the value of meff for Ca3 (Mn2 Nb)O9 to help assign oxidation states to Mn and Nb
in Ca3 (Mn2 Nb)O9 and explain why this compound is ferrimagnetic at low temperatures, calculating its saturated magnetic moment. Suggest why T N is noticeably lower
in this material than for either CaMnO3 or LaMnO3 .
(c) Ca3 (Mn2 Nb)O9 shows moderate electrical conductivity in the paramagnetic state, the
conductivity being thermally activated. In contrast, CaVO3 is metallic, the conductivity being essentially temperature independent. Briefly explain the mechanisms that
give rise to conductivity in these compounds, drawing appropriate MO/band diagrams
to explain this and commenting on the low measured value of meff for CaVO3 .
Approximate division of marks: (a) 40%, (b), 30%, (c) 30%.
11
SECTION C
M4 Energy Landscapes and Soft Materials
22
Consider the master equation that describes the time evolution of the occupation probabilities Pa (t), Pb (t), etc. for nmin local minima:
dPa (t) X
=
[kab Pb (t) kba Pa (t)]
dt
b,a
(1)
where kab is the rate constant for transitions from minimum b to minimum a.
(a) Show how a symmetrised form of the master equation
de
P(t) f e
= W P(t)
dt
p
ea (t) = Pa (t)/ Peq
can be obtained using the transformation of variables P
a , etc., where
eq
Pa is the equilibrium occupation probability of minimum a, specifying the matrix
e ab in terms of the equilibrium occupation probabilities and rate constants.
elements W
(b) Outline the steps involved in deriving the analytical solutions to equation (1) as
q X
X
P
(0)
c
eq
Pa (t) = Pa
uab eb t ucb p eq
Pc
c
b
where the quantities a and uab should be defined. Full mathematical details of the
derivation are not required.
(c) Now consider a system with three local minima, A, B, and C, with equal equilibrium
occupation probabilities and kAA = kBB = kCC = kAC = kCA = 0, kAB = kBA = 1, and
kBC = kCB = k, with k small compared to one. Show that the eigenvalues of f
W are
0, and approximately 2 and 3k/2. (Hint: the zero eigenvalue can be factored from
the determinant before expanding.) Describe the corresponding relaxation processes
in this three-state system.
Given that the corresponding eigenvectors are
(1, 1, 1)/ 3, (1, 1, 0)/ 2 and (1, 1, 2)/ 6

show that PC (t) (1 exp(3kt/2))/3 if PA (0) = 1 and PB (0) = PC (0) = 0.
[TURN OVER
12
23
Consider two solid plates immersed in a solution of ideal polymers whose radius of
gyration is Rg . The polymers can interpenetrate each other, but cannot overlap with the
plates. The plates do not interact with each other unless their surface-to-surface distance,
r, is less than 2Rg . In that case polymers are excluded from the volume between the plates,
and the plates feel an effective attractive force per unit area:
= p kT
(1)
where p is the polymer number density. This result can be intuitively understood as the
force due to the osmotic pressure of the polymers, pushing on the plates from the outside.
(a) Show that the interaction energy per unit area of two plates at a distance r < 2Rg is
given by
Wplateplate (r) = p kT (2Rg r)
if 0 < r < 2Rg
(2)
(b) Now consider a flat solid wall interacting with a hard spherical colloid with radius R,
both immersed in the polymer solution from (a). Use the Derjaguin approximation to
show that the depletion interaction energy between the wall and the colloid is given
by:
Uwallcolloid (r) = p kT R(2Rg r)2
if 0 < r < 2Rg
(3)
where r is the closest distance between the surface of the wall and the surface of the
colloid.
(c) We can also compute the effective colloidwall interaction without making use of
the Derjaguin approximation. To this end we make use of the fact that the effective
colloidwall interaction potential, in the presence of the polymer solution, can be
expressed as:
Ueff (r) = U0 (r) 1 z p Veff (r)
(4)
where U0 (r) is the interaction potential in the absence of polymers, Veff (r) is the
volume accessible to the polymers when the wallcolloid distance is r, = 1/kT
and z p = exp( p ) = p , where p is the polymer chemical potential. Compute the
volume accessible to the polymers as a function of the colloidwall distance, Veff (r),
and show that for r > 0, the effective wallcolloid interaction is give by:
Uwallcolloid (r) = 1 z p (2Rg r)2 (3R + RG + r)

3
(5)
13
a
h
h2
[Hint: The volume of a spherical cap with height h is Vcap =
(3a h), where a is
3
the radius of the sphere; see figure above.]
(d) In which case does Eq. (5) simplify to Eq. (3)? Explain the conditions for which the
Derjaguin approximation valid.
(e) Colloidal suspensions are sometimes stabilised against coagulation by adding
adsorbing polymers to the suspension. Explain under what conditions polymers can
stabilise the suspension rather than promoting its aggregation.
Approximate division of marks: (a) 25%, (b) 25%, (c) 25%, (d) 15% (e) 10%.
[TURN OVER
14
SECTION D
M5 Stereocontrolled Organic Synthesis
24
This reaction sequence outlines Kims synthesis of the cladiellin diterpene A.
O
O
O
OPMB
N
Bn
OH
* *
OPMB
Bn
[PMB = p-MeO(C6H4)CH2]
Me2N
Me2N
O
O
LiN(SiMe3)2, THF
TBDPSO
Cl
OTr
E
[TBDPS = tBuPh2Si;
Tr = CPh3]
TBDPSO
TrO
MeO
HO
O
TrO
H TrO
xylene, reflux
H H
H H
O
HH
OH
A
*
* *
O
HH
TrO
MeO2C
I
15

(a) Suggest a synthesis of the chiral building block B. Suggest suitable reagents and
conditions for performing the transformation B + C D, and explain the origins of
the control at the marked stereocentres (*).
(b) Account mechanistically for the transformation E F.
(c) Suggest suitable reagents and conditions for performing the transformation G H.
(d) Account mechanistically for the transformation H I and the high level of control
over the new stereocentres generated.
Approximate division of marks: (a) 35%, (b) 20%, (c) 20%, (d) 25%.
[TURN OVER
16
25
(a) Give a mechanistic account of the reaction shown below.
O
OH
O
OTf
EtO P
EtO
OEt
LDA (2 eq.)
OEt
(b) Give a mechanistic account of the process shown below, which includes a pericyclic
reaction
i) CsF
TMS
Boc
Cl
ii)
Boc
EtO2C
N
CO2Et
(c) Give a mechanistic account of the reaction shown below.
O
S
O
S
O
CO2Me
Ph
N
DABCO
O
S
O
Ph
Ph
S
O
O
O O
S
S
Ph
DBU
N
Ph
CO2Me
MeO2C
Ph
17

(d) Give a mechanistic account of the process shown below.
O
CHO
N
Br
N Ph
OH
Ph
H
O
O
Na
Ph
Ph
(e) Give a mechanistic account the process shown below, which includes a pericyclic step
O
O
S
Ph
N
Ts
F3C
TMS
O
O
CF3
Ph
N
Ts
[TURN OVER
18
SECTION E
M6 Computer Simulation Methods in Chemistry and Physics
26
The one-dimensional Ising model is defined by
X
X
E = J
si sj B
si
hi ji
where E is the energy of a system of spins si , J is a coupling constant and B is an external

magnetic field, and for which si can take the values +1 and 1. In one dimension each
spin has two neighbours, one on the left and the other on the right. The symbol hi ji in the
first sum indicates that the sum is restricted to immediate neighbouring pairs of spins.
(a) Find a simple expression for the partition function
X
X
Z=
exp J
si sj
{si }
hi ji
for a system of N spins with free boundary conditions (i.e. for which spin 1 has only
spin 2 as a neighbour, and spin N has only spin N 1 as a neighbour). The first sum
runs over all the possible values of the si variables and is the inverse temperature.
Note that
X
exp (Jsi si+1 ) = 2 cosh J
si
(b) Find the free energy F from the partition function.

(c) Find the specific heat C as a derivative of the free energy
2 F
C= 2
(d) Compare the previous expression for C with that derived from the fluctuations of the
energy
hE 2 i hEi2
C=
kB T 2
19
27
The autocorrelation function of a function f (x) is defined as
Z
C(x) =
dx0 f (x0 ) f (x + x0 )
(a) Describe the behaviour of C(x) for small and for large values of x.
(b) When the function f (x) is the velocity of a particle in a fluid (i.e. f (x) = v(t), where
v is the velocity and t is the time), describe the behaviour of C when the temperature
approaches the freezing point.
(c) The Fourier transform of a function f (x) is defined as
Z
1
F(k) =
f (x) exp (ikx) dx
2
Show that the autocorrelation function C(x) of f (x) can be obtained as the inverseFourier transform of the modulus square of the Fourier transforms of f (x).
[TURN OVER
20
SECTION F
M7 Nano Science and Colloid Science Chemistry at small length scales
28
(a) Starting from the Gibbs adsorption equation
d =
i di
Show that for a non-ionic surfactant in water this can be written:

d
= RT 0i
d ln Ci
where is the surface tension, Ci the concentration and i is the chemical potential
of species i. Explain the symbols i and 0i , including the significance of the prime.
State clearly any assumptions you make.
(b) The surface tension for solutions of a non-ionic surfactant C12 EO6 in water at 25 C
are given below.
conc / mM
0.0002
0.001
0.005
0.025
0.05
0.065
0.2
0.5
/ mN m1
65
60
53
42
35
32
32
32
By plotting a suitable graph, estimate the Critical Micelle Concentration (CMC)

of this surfactant. Compare your answer for C12 EO6 with the CMC of SDS
(8 103 mol dm3 ). Estimate the surface area per molecule of the surfactant in a
micelle, justifying your approach and commenting on your answer.
(c) A Volmer plot of a similar surfactant with a much longer alkyl chain gives a surface
area per molecule of 35 2 . Explain why a much longer alkyl chain is required in this
study. Explain the differences in area per molecule obtained by the Volmer method
and the Gibbs adsorption isotherm method.
In what situations would you expect them to be similar in magnitude?
(d) Given that the bulk density of C12 EO6 is 0.95 g cm3 , estimate the molecular volume
of each surfactant molecule. The fully extended C12 hydrocarbon chain is 1.668 nm
in length. What is the most likely micelle shape adopted by this surfactant? Estimate
the aggregation number these micelles, justifying your answer.
21

(e) How would you expect this micelle shape to change on cooling the system? Justify
your answer.
(f) Certain surfactants adsorb on a solid surface as lines of cylinders. Compare the
information you could obtain on this system using neutron reflection with that
obtainable using Atomic Force Microscopy (AFM).
Approximate division of marks: (a) 20%, (b) 30%, (c) 20%, (d) 10%, (e) 10%, (f) 10%.
[TURN OVER
22
29
(a)
(i) The radius of gyration of a polymer is 1/ 6 of the average root mean square
end to end distance. A polystyrene chain with a molecular weight of 105 g/mol
has a radius of gyration of 6.7 nm in cyclohexane at 34.5 C, the theta temperature.
Estimate the radius of gyration for a chain with a molecular weight of
5 105 g/mol under the same solution conditions.
(ii) Now the temperature of the system is increased to 45 C. Do you expect the
radius of gyration of the polymer to increase or decrease? Explain your answer.
(iii) By making use of (ii), give the radius of gyration of the 5 105 g/mol and
105 g/mol samples from (i) at 45 C. You may assume that the effective size
of the monomer unit does not change and that the radius of gyration remains
related to the root mean square end-to-end distance as in (i).
(iv) Give an example of a measurement that would allow your predictions in (iii) to
be tested.
(i) The graph below gives sum generation spectra resulting from the treatment of
a polydimethylsiloxane (PDMS) surface with an oxygen plasma. Draw out the
structure of PDMS.
sum frequency generation (arbitrary units)
(b)
23

(ii) Which part of the sample does the signal originate from? Give your reasoning.
(iii) During the plasma treatment, the intensity of the methyl peak decreases while a
peak corresponding to silenol groups appears. Would you expect this change to
increase or decrease the contact angle of a water droplet on the PDMS surface.
Illustrate your reasoning with a diagram that defines the contact angle.
Approximate division of marks: (a) (i) 15%, (ii) 10%, (iii) 15%, (iv) 15%, (b) (i) 10%,
(ii) 15%, (iii) 20%.
[TURN OVER
24
SECTION G
M8 Protein folding, misfolding and disease
30
Many intermediate states are only transiently populated during protein folding.
(a) How is it possible to detect the presence of an intermediate state during folding?
(b) Briefly describe two experimental strategies that can be used to characterise intermediate states. Use diagrams whenever possible to illustrate your answer.
A knotted protein X is known to fold through an intermediate state. The chevron plot
showing the rate constants of the unfolding and refolding phases is shown below.
(c) Why is only one unfolding phase observed but two refolding phases? Use energy
diagrams to illustrate your answer.
In order to obtain more information on the unfolding/refolding pathway of protein X, a
double-jump experiment was performed. In this experiment, denatured protein was mixed
rapidly with native buffer to induce folding. It was left for some ageing time, tage , before
being rapidly being mixed back into unfolding conditions. The unfolding kinetics were
measured.
(d) How would the unfolding kinetics of this double-jump experiment differ from those
observed in the single-jump experiment? What would be observed at (i) very short
ageing times, (ii) intermediate ageing times and (iii) very long ageing times?
25

(e) Illustrate how the amplitudes of the two unfolding phases observed in the doublejump experiment would vary with tage .
(f) On the diagram you have drawn for part (e) indicate which rate constants can be
extracted.
Approximate division of marks: (a) 20%, (b) 20%, (c) 20%, (d) 20%, (e) 10%, (f) 10%.
[TURN OVER
26
31
(a) -value analysis is often used to determine the mechanism for protein folding. What
biophysical parameters would you need to know to determine a -value for any
residue in the protein? Give the units for these parameters. Give the equations needed
to determine from experimentally determined biophysical parameters.
(b) A new class of proteins, called intrinsically disordered proteins (IDPs), have
recently been identified; many of these fold upon binding another macromolecule
(e.g. nucleic acid or protein ligand). There are two possible extreme mechanisms of
folding upon binding. What are these mechanisms? Explain why a change in IDP
concentration might cause a switch from one mechanism to the other.
(c) In studies of IDP folding upon binding, a number of biophysical parameters can
be obtained: kon , association rate constant; koff , dissociation rate constant; Kd ,
equilibrium dissociation constant; and G, the change in free energy for the overall
reaction. Which of these parameters can be directly compared to the parameters
obtained in a protein folding experiment? Explain your answer.
27

A -value analysis has been performed for the binding of an IDP, PUMA, to a target
protein M. PUMA forms a long helix on binding to M. Mutations were made in the
PUMA peptide. Two types of -values were obtained: surface Ala-to-Gly mutations, and
mutations of residues that are buried in the interface with protein M.
(d) The results are given in the table below. In this system association / dissociation is
apparently two-state and the equilibrium parameters were determined from the ratios
of the association (kon ) and dissociation (koff ) rate constants. Determine the -value
for the mutation L14A. Assume that RT = 0.59 kcal mol1 .
(e) From the pattern of -values describe the structure of the complex between PUMA
and protein M in the transition state. What is the likely mechanism of binding of
PUMA to M? Explain your reasoning.
variant of PUMA
position of residue
in complex
kon (s1 M1 )
koff (s1 )
7.7 106
1.39 103
WT
A4G
surface
0.12
W6F
buried
0.27
A9G
surface
0.34
I10A
buried
0.38
A12G
surface
0.37
L14A
buried
A16G
surface
0.04
A20G
surface
0.02
L22A
buried
0.05
A24G
surface
0.02
Y26A
buried
0.01
2.8 106
1169 103
Approximate division of marks: equal for each part.
[TURN OVER
28
SECTION H
M9 Supramolecular Chemistry and Self-assembly
32
The reaction between equimolar amounts of A, B and zinc(II) acetate (shown below) in
isopropanol at 70 C for 3 h produced three products 1, 2 and 3 as shown below. These
three products each had an intense peak with many isotopomeric sub-peaks centred close
to m/z = 295 in the high-resolution ESI mass spectrum.
NH2
1
N
O
O
B
N
N
Zn(O2CCH3)2
3
O
NH2
A
For each of 1, 2 and 3, the principal m/z = 295 peak was analysed and the separation
between isotopomers was determined. In each case the species giving rise to the principal
peak was separated using a Fourier-Transform Ion Cyclotron Resonance (FT-ICR) mass
spectrometer, and was subjected to fragmentation in a MSMS experiment. 1 H NMR
spectra were acquired from each of 1, 2 and 3, and in each case there were seven signals
in the aromatic region.
(a) For 1, the principal m/z = 295 peak revealed a separation of 0.25 daltons between
isotopomers. This species was observed to fragment cleanly into species having
m/z = 295 (spacing 0.5 daltons), m/z = 557 (spacing 0.5 daltons), and m/z = 526
(spacing 1 dalton).
Provide a structure for 1. Explain briefly how it is consistent with the MS and NMR
observations noted above.
(b) How many 1 H NMR signals would you expect to observe for CH2 protons in product
1? Would any of these signals be expected to show 1 H1 H coupling to each other?
Briefly explain your reasoning.
29

(c) For 2, the principal m/z = 295 peak revealed a separation of 0.167 daltons between
isotopomers. This species was not observed to fragment cleanly in MSMS, in
contrast to what was observed in the case of 1.
(d) How many 1 H NMR signals would you expect to observe for CH2 protons in product
(e) For 3, the principal m/z = 295 peak revealed a separation of 0.125 daltons between
isotopomers. This species was observed to fragment cleanly into species having
m/z = 164 (spacing 0.125 daltons), 207 (spacing 0.167 daltons), 295 (spacing 0.25
daltons), m/z = 557 (spacing 0.5 daltons), and m/z = 1051 (spacing 1 dalton).
(f) How many 1 H NMR signals would you expect to observe for CH2 protons in product
(g) Product 3 is formed in much lower amounts than either 1 or 2. At low concentrations, it disappears during equilibration in favour of 1 and 2. Briefly explain this
observation.
Approximate division of marks: (a) 20%, (b) 10%, (c) 20%, (d) 10%, (e) 20% (f) 10%,
(g) 10%.
[TURN OVER
30
33
Coronene (1 below) is observed to bind to the hexafluorophosphate salt of tetracationic
cyclophane 2 (below) with an association constant Ka = 6105 M1 to form a 1:1 adduct 3.
1
2
(a) Show or describe briefly the structure of the adduct 3.

(b) Name three techniques that could be used to measure Ka , briefly describing the
experimental procedure involved in each case.
31

(c) In the 1 H NMR spectrum of ethylcorannulene (4 below) at 200 K the CH2 protons
give rise to two doublets of quartets. At 300 K the CH2 protons produce a single
quartet. Briefly explain these observations.
Ethylcorannulene 4 and cyclophane 2 were observed to associate to form an adduct 5, with

Ka = 6 103 M1 . In the 1 H NMR spectrum acquired at temperatures of 200 K or greater,
the CH2 protons of 4 in adduct 5 produce a single quartet.
(d) Briefly explain why the affinity of 2 for 4 is two orders of magnitude less than the
affinity of 2 for 1.
(e) In light of your answers to (c) and (d) above, briefly explain why the CH2 protons of
4 in adduct 5 produce a single quartet at temperatures above 200 K.
[TURN OVER
32
SECTION I
M10 Medicinal Chemistry
34
(a) Multicomponent reactions can rapidly build up complexity in target molecules, in
many cases containing heterocycles. The scheme shown below shows one such
reaction scheme, in which a tetrahydropyrano-quinolone derivative A is synthesised.
Provide a mechanism for this three-component process with ammonium acetate as a
promoter:
H
N
Ph
CN
+
PhCHO
NC
CN
HN
NH4OAc
EtOH
OH
(b) In the reaction below, the thieto-quinoline ring system B was the main product at
room temperature (75%). However, at elevated temperature a significant proportion
(35%) of the thieno-quinoline side-product C was formed. It was then found that, if
heated under the same reaction conditions, thieto-quinoline product B rearranges to
form the thieno-quinoline C in high yield.
N
NH2
S
H
O
+
10% KOH
in EtOH
RT (75%)
10% KOH in
EtOH, (94%)
(35%)
N
C
S
S
(i) Suggest a mechanism for the formation of the thieto-quinoline product B.

(ii) Suggest a mechanism by which the rearrangement may occur to give thienoquinoline side-product C from B.
NH2
33

(c) The 2-acylindole is found in many natural products and biologically active molecules
and there are many methods by which this important structural motif may be accessed.
One of the most recent provides a way in which to synthesise both this and the
2-acylindoline congener by changing the protecting group on the nitrogen atom in
the starting material.
O
D
I2, K2CO3, MeOH, 60 C
N
H
PG = Ts
R
PG
N
I2, K2CO3, MeOH, RT
PG = Boc
O
E
N
Boc
(i) Provide a mechanism for the formation of products D and E.

(ii) Give two other methods by which an indole may be produced which is functionalised in the 2-position (no mechanisms required), one from a starting
material in which the indole core is already in place, the other generating the
2-functionalised indole product from a non-indole precursor.
(d) Varenicline, better known in the UK as Champix, is a highly successful smoking
cessation aid. It can be made from the DielsAlder product F as summarised below:
N
NH
N
Champix (G)
(i) Provide a synthesis of Champix G from intermediate F and any other available
reagents/starting materials you choose. Mechanisms are not required.
(ii) Is Champix chiral? Briefly outline the advantages and disadvantages of having
a chiral vs an achiral drug molecule.
[TURN OVER
34
35
(a) Rimonabant is a central cannabinoid receptor 1 (CB-1) antagonist.
R1
O
Cl
N
R2HN
Cl
Rimonabant core J
(i) Propose a synthetic route to the Rimonabant core J from the indicated starting
material and other reagents/starting materials you choose. Mechanisms are not
required.
(ii) Explain the difference between an agonist and an antagonist.
(iii) Within three years Rimonabant was withdrawn from the market. Outline why
this is an unusual event and why it sometimes happens.
(b) Consider the following reaction scheme: draw structures for H and I, and write a
mechanism for the formation of H.
O
N
H2, Pd/C
H
85 C
OMe
(C14H19NO2)
I
(C14H21NO2)
max 3400cm-1 (broad)
35

(c) 1,2,4-Triazoles are found in a wide range of biologically active molecules encompassing several therapeutic areas. A method for their synthesis has been developed
recently using the multicomponent reaction process shown below:
R
NH2
R
NOTs
HC(OEt)3
N
N
NH2
(i) Give a mechanism for the reaction.

(ii) How would you establish which nitrogens of the starting materials end up at
which positions in the product?
(d) Quetiapine K is an antipsychotic treatment for schizophrenia. Propose a synthesis
of it from ortho-chloronitrobenzene. You may assume that this and mono-substituted
piperazines/aromatic rings are available: other standard reagents and solvents may be
selected and applied to your synthesis (no mechanistic details are required):
S
Cl
?
NO2
Quetiapine K
N
N
N
R
END OF PAPER

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NATURAL SCIENCES TRIPOS Part III

Monday 26th May 2014

You may not start to read the questions printed on

[Continuation of Qu. 18]

[Continuation of Qu. 19]

Complex F is made by combination of anion A with cation B. Complex G has the

[Qu. 20 continued on next page]

[Continuation of Qu. 20]

[Qu. 20 continued on next page]

[Continuation of Qu. 20]

Approximate division of marks: (a) 30%, (b) 40%, (c) 30%.

Rationalize the Weiss constants, magnetic properties and CurieNeel temperatures

[Continuation of Qu. 21]

(1, 1, 1)/ 3, (1, 1, 0)/ 2 and (1, 1, 2)/ 6

Uwallcolloid (r) = 1 z p (2Rg r)2 (3R + RG + r)

[Continuation of Qu. 23]

[Qu. 24 continued on next page]

[Continuation of Qu. 24]

(c) Give a mechanistic account of the reaction shown below.

[Qu. 25 continued on next page]

[Continuation of Qu. 25]

where E is the energy of a system of spins si , J is a coupling constant and B is an external

(b) Find the free energy F from the partition function.

Approximate division of marks: (a) 20%, (b) 20%, (c) 60%.

Show that for a non-ionic surfactant in water this can be written:

By plotting a suitable graph, estimate the Critical Micelle Concentration (CMC)

[Continuation of Qu. 28]

sum frequency generation (arbitrary units)

[Qu. 29 continued on next page]

[Continuation of Qu. 29]

[Continuation of Qu. 30]

[Continuation of Qu. 31]

Approximate division of marks: equal for each part.

[Continuation of Qu. 32]

(a) Show or describe briefly the structure of the adduct 3.

[Continuation of Qu. 33]

Ethylcorannulene 4 and cyclophane 2 were observed to associate to form an adduct 5, with

(i) Suggest a mechanism for the formation of the thieto-quinoline product B.

[Continuation of Qu. 34]

I2, K2CO3, MeOH, 60 C

I2, K2CO3, MeOH, RT

(i) Provide a mechanism for the formation of products D and E.

[Qu. 35 continued on next page]

[Continuation of Qu. 35]

(i) Give a mechanism for the reaction.

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