iii 2014 paper2

7/25/2019 III 2014 Paper2

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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 di ff erent sections.

Where a question is divided into sections, the approximate division of marks betweensections 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 inthe 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 SPECIAL REQUIREMENTS

Graph paper (2 sheets) Department of Chemistry Data BookLined paper Question record card

Rough work pad

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.

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SECTION A

M2 Advanced Di ff raction Methods

18

Answer all parts of the question.

(a) “Electron diff raction is an extremely useful technique in the identification of un-known materials but nevertheless is a poor method of determining the exact atomicstructure”. Bearing in mind the strength of the interaction of electrons with mattercompared 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 formusing sol-gel methods, but crystals of a size large enough for single-crystal diff ractionstudies cannot be grown without converting to the high-temperature phase. Whenexamined by electron diff raction, three principal reciprocal lattice patterns can beobtained.

Pattern A shows an orthogonal arrangement of diff raction maxima, with spot sep-arations measured as 2.471 and 2.410 mm; pattern B is also orthogonal, with spotseparations 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 spotsbeing 80.8◦.

If the camera length is 50 cm, and the patterns are recorded with 200 kV electrons(λ = 0.0251 Å), calculate the unit cell parameters of HfO2. In labelling the axes, youshould 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 separation2.410 mm are invariably very weak, and a similar eff ect 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]

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[Continuation of Qu. 18]

(d) The x-ray powder diff raction pattern is complex but can be indexed once the unit celldimensions are known. When the line intensities are measured, these can then beused to determine the structure. If CuKα radiation (λ = 1.5418 Å) is used, two verystrong lines are noted at 2θ = 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 exper-imental factors) are found to be 207 and 227. If there are four hafnium atoms in theunit cell and the space group is assumed to be P21 / c these will occupy positions withcoordinates ±( x, y, z) and ±( x, 12 − 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 thesevalues of sin (θ )/λ the scattering factor of hafnium is approximately 60 electrons.

(e) Once approximate hafnium atomic coordinates are known, how could you then refinetheir values and how would you locate the oxygen atoms?

Approximate division of marks: (a) 20%, (b) 20%, (c) 10%, (d) 30%, (e) 20%.

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(a) For a weak phase object (i.e. amplitude scattering can be neglected) show that theimage intensity from a periodic specimen with a centre of symmetry can be writtenin the form:

II(r ) = 1 − 4σ+Sn

V (Sn) × cos (2πr.Sn) × sin ( χ(Sn))

where σ is an interaction parameter, V (Sn) are the Fourier coefficients of the projectedpotential in the specimen, and sin ( χ(Sn)) is the Phase Contrast Transfer Function,(PCTF), given by:

sin ( χ(Sn)) = sin2πλ

12 ∆F λ2S2

n − 14C sλ

4S4n

(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 frequentlynot possible. Indicate how this problem may be solved by Fourier transformationof the image intensity, and describe the two main problems which are commonlyencountered if this is attempted.

(c) An attempt is made to determine the structure of a zeolite membrane by high resolu-

tion electron microscopy. Because the specimen is extremely sensitive to electronbeam irradiation, it is necessary to carry out the examination in a liquid heliumcooled specimen holder, which, because of its bulk, necessitates a large pole-piecegap and consequently a comparatively large spherical aberration coefficient. Theimages therefore contain a considerable amount of detail but cannot be interpreteddirectly in terms of any known zeolite structure.

In order to solve the problem, a series of three images is taken, with a constant focusincrement δF 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 χ(S(hkl))

describe algebraically how you would actually deduce the defocus increment δF andhence the value of sin

χ(S(hkl))

for a given peak in the power spectrum, and thus

calculate the correct Fourier coefficient. You may assume that no allowance forchromatic aberration is necessary.


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(d) When this operation is performed on the zeolite images it is noted that some veryweak peaks are observed in the power spectrum at high S(hkl) values and these appearto be completely unaff ected by alteration of objective lens defocus. Suggest howthese weak peaks could arise, and why they are independent of focus position. Wouldyou expect them to contribute to the correct contrast of the image?

Approximate division of marks (a) 20%, (b) 20%, (c) 40%, (d) 20%.

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SECTION B

M3 Magnetic Materials

20


(a) Three new magnetic materials F, G and H have been prepared by combining an-ionic complexes containing Fe3+ anions with cationic species containing variousmanganese fragments. In all materials the iron and manganese are bridged by thecyanide ligands which are part of the Fe-anionic complex.

NN

N

O

Fe

N

NN

N N

O OMn

NNNN

A B

C D

N N

O O

Mn

E

Complex F is made by combination of anion A with cation B. Complex G has theformula [A]4[Mn(D)(MeOH)]2 and complex H has the formula [A]2[Mn(C)2]; bothG and H contain Mn2+. The connectivity of the metal ions in compounds F, G and H

is shown below.

A Fe

Mn

Fe

Mn

Mn

Fe

Mn Fe

Mn

Fe

Mn Fe

Mn

Fe

Mn Fe

Fe Mn Fe

Fe Mn

Fe

connectivity in F connectivity in G connectivity in H

Mn

Fe


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The magnetic susceptibilities of all three compounds are shown in the graphs below.For all three compounds use the limiting high-temperature value of χT to determine

the spin state of the ions.

F

G

H


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(b) A further compound, I, which has formula [A][E] can be prepared which has a simplealternating Fe–Mn chain containing Mn3+. Briefly explain how the Bonner–Fisherapproach 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 measurementcould be used to confirm this assignment?

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

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(a) A double perovskite Ca3(Mn2Nb)O9 (i.e. A3BB2O9) that contains two diff erent ions

(Mn and Nb) on the B site of the perovskite structure has been synthesized andinvestigated for its magnetoresistance and other electronic / magnetic properties. Somemagnetic properties of this material are compared with those of three simpler ABO3

perovskites below. (AFM = antiferromagnetism; TIP = temperature independentparamagnetism)

structure Weiss

constant (K)magneticproperty

Curie / Neeltemperature (K)

meff per formulaunit ( µB)

CaMnO3 −472 AFM 125

LaMnO3 +52 AFM 140

CaVO3 TIP 0.14

Ca3(Mn2Nb)O9 −99 ferrimagnetic 40 8.8

Rationalize the Weiss constants, magnetic properties and Curie–Neel temperatures(T N) of CaMnO3 and LaMnO3, describing the dominant magnetic interactions thatgive rise to these properties.

Explain briefly what you would observe on lowering the temperature below T N in theneutron diff raction patterns of the two structures, commenting on any diff erences inthe magnetic unit cells of the two materials.


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(b) The B(B)O6 octahedral units are tilted in Ca3(Mn2Nb)O9, resulting in a monoclinicspace group P21 / n, with two diff erent B sites and unit-cell parameters of a = 5.40 Å,b = 5.48 Å, c = 7.61 Å, β = 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) 1

Mn 2d 0.5 0 0 0.65

Nb 2d 0.5 0 0 0.35

Mn 2c 0.5 0 0.5 0.68

Nb 2c 0.5 0 0.5 0.32

How many Ca and Mn ions are there per unit cell? Comment on the extent of cationordering of Mn and Nb over the two B sites of this perovskite structure.

Use the value of meff for Ca3(Mn2Nb)O9 to help assign oxidation states to Mn and Nbin Ca3(Mn2Nb)O9 and explain why this compound is ferrimagnetic at low tempera-tures, calculating its saturated magnetic moment. Suggest why T N is noticeably lowerin this material than for either CaMnO3 or LaMnO3.

(c) Ca3(Mn2Nb)O9 shows moderate electrical conductivity in the paramagnetic state, theconductivity being thermally activated. In contrast, CaVO3 is metallic, the conduc-tivity being essentially temperature independent. Briefly explain the mechanisms thatgive rise to conductivity in these compounds, drawing appropriate MO / band diagramsto explain this and commenting on the low measured value of meff for CaVO3.

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

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SECTION C

M4 Energy Landscapes and Soft Materials

22


Consider the master equation that describes the time evolution of the occupation probabil-ities Pa(t ), Pb(t ), etc. for nmin local minima:

dPa(t )dt

=ba

[k abPb(t ) − k baPa(t )] (1)

where k ab is the rate constant for transitions from minimum b to minimum a.

(a) Show how a symmetrised form of the master equation

dP(t )dt

= WP(t )

can be obtained using the transformation of variables Pa(t ) = Pa(t )/

Peqa , etc., where

Peqa is the equilibrium occupation probability of minimum a, specifying the matrix

elements W ab in terms of the equilibrium occupation probabilities and rate constants.

(b) Outline the steps involved in deriving the analytical solutions to equation (1) as

Pa(t ) =

Peqa

b

uab eλbt c

ucbPc(0)

Peqc

where the quantities λa and uab should be defined. Full mathematical details of thederivation are not required.

(c) Now consider a system with three local minima, A, B, and C, with equal equilibriumoccupation probabilities and k AA = k BB = k CC = k AC = k CA = 0, k AB = k BA = 1, andk BC = k CB = k , with k small compared to one. Show that the eigenvalues of

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 processesin 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.


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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 theplates. The plates do not interact with each other unless their surface-to-surface distance,r , is less than 2 Rg. In that case polymers are excluded from the volume between the plates,and the plates feel an eff ective attractive force per unit area:

Π = − ρ pkT (1)

where ρ p is the polymer number density. This result can be intuitively understood as theforce 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 < 2 Rg isgiven by

W plate–plate(r ) = − ρ pkT (2 Rg − r ) if 0 < r < 2 Rg (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 toshow that the depletion interaction energy between the wall and the colloid is givenby:

U wall–colloid(r ) = − ρ pkT π R(2 Rg − r )2 if 0 < r < 2 Rg (3)

where r is the closest distance between the surface of the wall and the surface of thecolloid.

(c) We can also compute the eff ective colloid–wall interaction without making use of the Derjaguin approximation. To this end we make use of the fact that the eff ectivecolloid–wall interaction potential, in the presence of the polymer solution, can beexpressed as:

U eff (r ) = U 0(r ) − β−1 z pV eff (r ) (4)

where U 0(r ) is the interaction potential in the absence of polymers, V eff (r ) is the

volume accessible to the polymers when the wall–colloid distance is r , β = 1/kT and z p = exp( βµ p) = ρ p, where µ p is the polymer chemical potential. Compute thevolume accessible to the polymers as a function of the colloid–wall distance, V eff (r ),and show that for r > 0, the eff ective wall–colloid interaction is give by:

U wall–colloid(r ) = −π

3 β−1 z p(2 Rg − r )2(3 R + RG + r ) (5)


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a

h

[Hint: The volume of a spherical cap with height h is V cap = πh2

3 (3a − h), where a is

the radius of the sphere; see figure above.]

(d) In which case does Eq. (5) simplify to Eq. (3)? Explain the conditions for which theDerjaguin approximation valid.

(e) Colloidal suspensions are sometimes stabilised against coagulation by adding

adsorbing polymers to the suspension. Explain under what conditions polymers canstabilise the suspension rather than promoting its aggregation.

Approximate division of marks: (a) 25%, (b) 25%, (c) 25%, (d) 15% (e) 10%.

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SECTION D

M5 Stereocontrolled Organic Synthesis

24


This reaction sequence outlines Kim’s synthesis of the cladiellin diterpene A.

?

F

[TBDPS = t BuPh2Si;

Tr = CPh3]

D

E

CB

LiN(SiMe3)2, THF

[PMB = p-MeO(C6H4)CH2]

*O N

OPMB

O O

Bn

+ O N

OPMB

O O

Bn

OH

*H

O

TBDPSO

O

OTr

Cl

Me2N

TBDPSO

O

TrO

O

Me2N

O

*

?

I

O

TrO

*

HO

G

xylene, reflux

O

TrO

*

HO

MeO

TrO

O

H

H

H

HMeO2C

O

H

H

H

H

OH

A

*


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(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 controlover the new stereocentres generated.

Approximate division of marks: (a) 35%, (b) 20%, (c) 20%, (d) 25%.

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25


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

OTf

OH

EtO P

OEt

OO

EtO

LDA (2 eq.)

O

OEt

(b) Give a mechanistic account of the process shown below, which includes a pericyclicreaction

NBoc

CO2Et

TMS S Cl

i) CsF

ii)

N S

EtO2C

Boc

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

PhCO2Me

OO

O

N

S

S

O

O

O

Ph

DABCO DBUS

MeO2C Ph

O O O

Ph

N

S

PhCO2Me

Ph

O

S

O

O

S

N


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(d) Give a mechanistic account of the process shown below.

CHO

O

Ph

N N

N

Ph

Br

O ONa

O

OH

H

Ph

OO

Ph

(e) Give a mechanistic account the process shown below, which includes a pericyclic step

N

SPh

O

Ts

F3C O CF3

O O

TMS N

SPh

Ts


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SECTION E

M6 Computer Simulation Methods in Chemistry and Physics

26


The one-dimensional Ising model is defined by

E = − J i j

si s j − B

i

si

where E is the energy of a system of spins si, J is a coupling constant and B is an externalmagnetic field, and for which si can take the values +1 and −1. In one dimension eachspin has two neighbours, one on the left and the other on the right. The symbol

i j

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

Z ={si}

exp

β J i j

si s j

for a system of N spins with free boundary conditions (i.e. for which spin 1 has onlyspin 2 as a neighbour, and spin N has only spin N − 1 as a neighbour). The first sumruns over all the possible values of the si variables and β is the inverse temperature.

Note that si

exp ( β J si si+1) = 2 cosh β J

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

(c) Find the specific heat C as a derivative of the free energy

C = ∂2F

∂β2

(d) Compare the previous expression for C with that derived from the fluctuations of theenergy

C = E 2 − E 2

k BT 2


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27


The autocorrelation function of a function f ( x) is defined as

C ( x) =

d x f ( x) f ( x + x)

(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 ), wherev is the velocity and t is the time), describe the behaviour of C when the temperatureapproaches the freezing point.

(c) The Fourier transform of a function f ( x) is defined as

F (k ) = 1√

2π

∞

−∞ f ( x)exp(−ikx) d x

Show that the autocorrelation function C ( x) of f ( x) can be obtained as the inverse-Fourier transform of the modulus square of the Fourier transforms of f ( x).


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SECTION F

M7 Nano Science and Colloid Science – Chemistry at small length scales

28


(a) Starting from the Gibbs adsorption equation

dγ = −

Γi d µi

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

dγ

d ln C i= −

RT Γi

where γ is the surface tension, C i the concentration and µi is the chemical potentialof species i. Explain the symbols Γi and Γ

i , including the significance of the prime.State clearly any assumptions you make.

(b) The surface tension for solutions of a non-ionic surfactant C12EO6 in water at 25 ◦Care given below.

conc / mM 0.0002 0.001 0.005 0.025 0.05 0.065 0.2 0.5

γ / mN m−1 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 C12EO6 with the CMC of SDS(8 × 10−3 mol dm−3). Estimate the surface area per molecule of the surfactant in amicelle, justifying your approach and commenting on your answer.

(c) A Volmer plot of a similar surfactant with a much longer alkyl chain gives a surfacearea per molecule of 35 Å2. Explain why a much longer alkyl chain is required in this

study. Explain the diff erences in area per molecule obtained by the Volmer methodand the Gibbs adsorption isotherm method.

In what situations would you expect them to be similar in magnitude?

(d) Given that the bulk density of C12EO6 is 0.95 g cm−3, estimate the molecular volumeof each surfactant molecule. The fully extended C12 hydrocarbon chain is 1.668 nmin length. What is the most likely micelle shape adopted by this surfactant? Estimatethe aggregation number these micelles, justifying your answer.


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(e) How would you expect this micelle shape to change on cooling the system? Justifyyour answer.

(f) Certain surfactants adsorb on a solid surface as lines of cylinders. Compare theinformation you could obtain on this system using neutron reflection with thatobtainable using Atomic Force Microscopy (AFM).

Approximate division of marks: (a) 20%, (b) 30%, (c) 20%, (d) 10%, (e) 10%, (f) 10%.

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(a) (i) The radius of gyration of a polymer is 1/√ 6 of the average root mean squareend to end distance. A polystyrene chain with a molecular weight of 10 5 g / molhas a radius of gyration of 6.7 nm in cyclohexane at 34.5 ◦C, the theta temper-ature.

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 theradius 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 and105 g / mol samples from (i) at 45 ◦C. You may assume that the eff ective sizeof the monomer unit does not change and that the radius of gyration remainsrelated 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) tobe tested.

(b) (i) The graph below gives sum generation spectra resulting from the treatment of a polydimethylsiloxane (PDMS) surface with an oxygen plasma. Draw out thestructure of PDMS.

s u m f r

e q u e n c y

g e n e r a t i o n ( a r b i t r a r y u n i t s )


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(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 apeak corresponding to silenol groups appears. Would you expect this change toincrease 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%.

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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 interme-diate states. Use diagrams whenever possible to illustrate your answer.

A knotted protein X is known to fold through an intermediate state. The chevron plotshowing 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 energydiagrams to illustrate your answer.

In order to obtain more information on the unfolding / refolding pathway of protein X, adouble-jump experiment was performed. In this experiment, denatured protein was mixedrapidly with native buff er to induce folding. It was left for some ageing time, t age, beforebeing rapidly being mixed back into unfolding conditions. The unfolding kinetics weremeasured.

(d) How would the unfolding kinetics of this double-jump experiment diff er from thoseobserved in the single-jump experiment? What would be observed at (i) very shortageing times, (ii) intermediate ageing times and (iii) very long ageing times?


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(e) Illustrate how the amplitudes of the two unfolding phases observed in the double- jump experiment would vary with t age.

(f) On the diagram you have drawn for part (e) indicate which rate constants can beextracted.

Approximate division of marks: (a) 20%, (b) 20%, (c) 20%, (d) 20%, (e) 10%, (f) 10%.

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31


(a) Φ-value analysis is often used to determine the mechanism for protein folding. Whatbiophysical parameters would you need to know to determine a Φ-value for anyresidue in the protein? Give the units for these parameters. Give the equations neededto determine Φ from experimentally determined biophysical parameters.

(b) A ‘new’ class of proteins, called intrinsically disordered proteins (IDPs), haverecently 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: k on, association rate constant; k off , dissociation rate constant; K d,equilibrium dissociation constant; and ∆G, the change in free energy for the overallreaction. Which of these parameters can be directly compared to the parametersobtained in a protein folding experiment? Explain your answer.


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A Φ-value analysis has been performed for the binding of an IDP, PUMA, to a targetprotein M. PUMA forms a long helix on binding to M. Mutations were made in the

PUMA peptide. Two types of Φ-values were obtained: surface Ala-to-Gly mutations, andmutations 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 isapparently two-state and the equilibrium parameters were determined from the ratiosof the association (k on) and dissociation (k off ) rate constants. Determine the Φ-valuefor the mutation L14A. Assume that RT = 0.59 kcal mol−1.

(e) From the pattern of Φ-values describe the structure of the complex between PUMAand 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 k on (s−1 M−1) k off (s−1) Φ

WT 7.7 × 106 1.39 × 10−3

A4G surface 0.12

W6F buried 0.27

A9G surface 0.34

I10A buried 0.38A12G surface 0.37

L14A buried 2.8 × 106 1169 × 10−3

A16G surface 0.04

A20G surface 0.02

L22A buried 0.05

A24G surface 0.02

Y26A buried 0.01

Approximate division of marks: equal for each part.

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SECTION H

M9 Supramolecular Chemistry and Self-assembly

32


The reaction between equimolar amounts of A, B and zinc(II) acetate (shown below) inisopropanol at 70 ◦C for 3 h produced three products 1, 2 and 3 as shown below. Thesethree products each had an intense peak with many isotopomeric sub-peaks centred closeto m/ z = 295 in the high-resolution ESI mass spectrum.

A

B

1

N

N

O

O

NH2

NH2

N

O O

Zn(O2CCH3)2

2

3

For each of 1, 2 and 3, the principal m/ z = 295 peak was analysed and the separationbetween isotopomers was determined. In each case the species giving rise to the principalpeak was separated using a Fourier-Transform Ion Cyclotron Resonance (FT-ICR) massspectrometer, and was subjected to fragmentation in a MS–MS experiment. 1H NMRspectra were acquired from each of 1, 2 and 3, and in each case there were seven signalsin the aromatic region.

(a) For 1, the principal m/ z = 295 peak revealed a separation of 0.25 daltons betweenisotopomers. This species was observed to fragment cleanly into species havingm/ 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 NMRobservations noted above.

(b) How many 1H NMR signals would you expect to observe for CH2 protons in product1? Would any of these signals be expected to show 1H–1H coupling to each other?Briefly explain your reasoning.


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(c) For 2, the principal m/ z = 295 peak revealed a separation of 0.167 daltons betweenisotopomers. This species was not observed to fragment cleanly in MS–MS, incontrast to what was observed in the case of 1.


(d) How many 1H NMR signals would you expect to observe for CH2 protons in product2? Would any of these signals be expected to show 1H–1H coupling to each other?Briefly explain your reasoning.

(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 havingm/ z = 164 (spacing 0.125 daltons), 207 (spacing 0.167 daltons), 295 (spacing 0.25daltons), m/ z = 557 (spacing 0.5 daltons), and m/ z = 1051 (spacing 1 dalton).


(f) How many 1H NMR signals would you expect to observe for CH2 protons in product3? Would any of these signals be expected to show 1H–1H coupling to each other?Briefly explain your reasoning.

(g) Product 3 is formed in much lower amounts than either 1 or 2. At low concentra-tions, it disappears during equilibration in favour of 1 and 2. Briefly explain thisobservation.

Approximate division of marks: (a) 20%, (b) 10%, (c) 20%, (d) 10%, (e) 20% (f) 10%,(g) 10%.

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Coronene (1 below) is observed to bind to the hexafluorophosphate salt of tetracationiccyclophane 2 (below) with an association constant K a = 6×105 M−1 to form a 1:1 adduct 3.

1

N

N N

N

2

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

(b) Name three techniques that could be used to measure K a, briefly describing theexperimental procedure involved in each case.


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(c) In the 1H NMR spectrum of ethylcorannulene (4 below) at 200 K the CH2 protonsgive rise to two doublets of quartets. At 300 K the CH2 protons produce a singlequartet. Briefly explain these observations.

4

Ethylcorannulene 4 and cyclophane 2 were observed to associate to form an adduct 5, withK a = 6 × 103 M−1. In the 1H 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.


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SECTION I

M10 Medicinal Chemistry

34


(a) Multicomponent reactions can rapidly build up complexity in target molecules, inmany cases containing heterocycles. The scheme shown below shows one suchreaction scheme, in which a tetrahydropyrano-quinolone derivative A is synthesised.Provide a mechanism for this three-component process with ammonium acetate as apromoter:

HN

OH

O

+ PhCHO + NC CN NH4OAc

EtOH

HN

O

O Ph

CN

NH2

A

(b) In the reaction below, the thieto-quinoline ring system B was the main product atroom 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 toform the thieno-quinoline C in high yield.

H

O

NH2

+

S

O

10% KOH

in EtOH

N

S

RT (75%)

∆ (35%)

N

S

10% KOH in

EtOH, ∆ (94%)

B

C

(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 thieno-quinoline side-product C from B.


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(c) The 2-acylindole is found in many natural products and biologically active moleculesand 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 the2-acylindoline congener by changing the protecting group on the nitrogen atom inthe starting material.

NPG

H

R

OI2, K2CO3, MeOH, 60 ºC

PG = Ts

I2, K2CO3, MeOH, RT

PG = Boc

NH

R

O

N R

O

Boc

D

E

(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 func-tionalised in the 2-position (no mechanisms required), one from a startingmaterial in which the indole core is already in place, the other generating the2-functionalised indole product from a non-indole precursor.

(d) Varenicline, better known in the UK as Champix, is a highly successful smokingcessation aid. It can be made from the Diels–Alder product F as summarised below:

F Champix (G)

N

N

NH?

(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.


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(a) Rimonabant is a central cannabinoid receptor 1 (CB-1) antagonist.

N

N

O

R2HN

R1

Cl

Rimonabant core J

Cl

O

?

(i) Propose a synthetic route to the Rimonabant core J from the indicated startingmaterial and other reagents / starting materials you choose. Mechanisms are notrequired.

(ii) Explain the diff erence between an agonist and an antagonist.

(iii) Within three years Rimonabant was withdrawn from the market. Outline whythis is an unusual event and why it sometimes happens.

(b) Consider the following reaction scheme: draw structures for H and I, and write amechanism for the formation of H.

OMe

N

O

85 ºC

H

(C14H19NO2)

I

(C14H21NO2)

νmax 3400cm-1 (broad)

H2, Pd/C


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(c) 1,2,4-Triazoles are found in a wide range of biologically active molecules encom-passing several therapeutic areas. A method for their synthesis has been developedrecently using the multicomponent reaction process shown below:

R

NH2

NH2

NOTs

HC(OEt)3

R

N

N

N

(i) Give a mechanism for the reaction.

(ii) How would you establish which nitrogens of the starting materials end up atwhich positions in the product?

(d) Quetiapine K is an antipsychotic treatment for schizophrenia. Propose a synthesisof it from ortho-chloronitrobenzene. You may assume that this and mono-substitutedpiperazines / aromatic rings are available: other standard reagents and solvents may beselected and applied to your synthesis (no mechanistic details are required):

N

S

N

N

R

Cl

NO2

?Quetiapine K


END OF PAPER

iii 2014 paper2

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