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1. Cocaine, also known as benzoylmethylecgonine or coke, is a strong stimulant. It inhibits the ________
reuptake of neurotransmitters and hence increases their concentration in the brain.
Answer the following questions about the compound: (7.5 p = 71 p [a-e, g-h] + 10.5 p [f])

a) Give the hybridisation state for atoms c, d, e, f. sp3, sp3, sp2, sp2
b) Give the oxidation number for atoms d, e, f. -II, +III, -I
c) Draw a line through all bonds which can be hydrolysed under basic conditions. See red lines.
d) The compound contains 3 rings. Should the compound show absorption in the UV range
(Yes/No)? If any encircle the moiety(s) which is/are responsible for the absorption in the UV range.
Yes (see red circle)
e) What is/are the name(s) of the functional group(s) atoms e is part of? Ester (carbonyl)
f) What is the charge of the molecule at pH 7? 0
g) Which configurations have carbon atoms a and b according to the R/S-system (Cahn-Ingold-
Prelog)? R, R
h) Classify the amine. Tertiary amine
[Extra point alert: i) Draw the most stable conformer of cocaine? (1 p)]

Answer:
boat conformation of the piperidine and equatorial 2nd ring (obs stereochemistry
on the two esters
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2. a) What are U, W, X, Y, and Z in the following compound if it is assumed to contain the following
functional groups: primary amine, thioether and -ketoacid. (2.5 p)
b) What is the thermodynamic, entropic reasoning that heat is required in the decarboxylation of -
ketoacids? Explain. (1 p)

Answer:
a) X: OH, Y: O, W: O, U: S, Z: NH2
b) In the elimination 2 molecules are produced from one, so the entropy increases.
According to the 2nd law of thermodynamics (G=H-TS), G gets smaller, more
negative and the reaction more favourable the larger the second term. This
happens with higher temperature (when S is positive, as here).

3. Add (draw) free electron pairs, charges, multiple bonds etc. to the following ring system so that it
becomes aromatic. (1 p)

Answer
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4. The following molecule is the monoterpenoid geraniol. It is part of several natural oils and the ________
starting point in the synthesis of various other pleasant smelling compounds. Citronellol can be
synthesised from geraniol (or its isomer nerol) by selective hydrogenation and geranyl acetate by
esterification with acetic acid.
a) What is the name of geraniol according to IUPAC rules? The stereochemistry should become
evident from the name. (1.5 p)
b) Draw the R isomer of citronellol (Note: only the right alkene gets hydrogenated). (1 p)
c) Give a detailed, curved-arrow mechanism for the esterification of geraniol with acetic acid to
yield geranyl acetate, incl. all protonation and deprotonation steps and resonance structures. (4 p)

geraniol

Answers:
a) (trans/E)-3,7-dimethyl-2,6-octadien-1-ol
b)

c)
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5. Propose a sequence of reactions that will accomplish the following transformation. What are
conditions a, b and d and the intermediate C? Give the name of the overall reaction of b and d.
(2.5 p)

a: PCC
b: methyl amine (slightly acidic)

C:

d: H2 and metal catalyst

reductive amination
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6. Give structural formulas for the main products in the following reactions (clearly indicate the
stereochemistry in d). (4 1 p)

a)

b)

c)

d)
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7. A biomedical researcher obtains compound X as a side product in a synthesis and decided to ________
characterise it further. The following analyses were done:

a) Several mg were sent for elemental analysis and gave the molecular formula C4H8O2.

b) The following 1H-NMR spectrum and IR was obtained for compound X:

c) 5 mg are treated with H2SO4 which yields compound Y. The mass spectrum and IR spectrum of
Y are obtained:
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d) 5 mg of compound X are refluxed in ethanol in presence of base to yield compound Z. After

purification Z can be treated with base to synthesise compound Y. A 1H-NMR spectrum is
recorded for Z:

What are compounds X, Y, and Z (give names and structural formula)? Motivate your answer by
explaining all spectra and reactions (e.g. splitting in mass spectrum, downfield signal in NMR,
functional groups, reaction names, etc.)! (5 p)

Answer:
b) Singlet from ester methyl, triplet and quartet from the ethyl part
of the carbon chain. Singlet is downfield due to closeness of
oxygen, slightly downfield for quartet due to clones to carbonyl.
In IR the band at 1743 indicates a carbonyl, probably a
saturated aliphatic ester. (The bands at 3000-2850 indicate C-H
alkane stretches. The bands in the region 1320-1000 could be due
to C-O stretch, consistent with an ester.)
c) Under acidic condition the ester is cleaved and the carboxylic
acid is produced. The IR shows C O peak at wavenumber 1000
to 1300. There is a peak at 1640 to 1750 wavenumber indicating
a C=O bond. There is a very broad peak at wavenumber 2500 to
3300 indicating a O H bond. Molecular ion at m/z 74, ethyl at
29, CO2H at 45. Loss of OH gives CH3-CH2-CO+, m/z 57.
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d) Transesterification with ethanol to give ethyl ester. Which then
can be hydrolysed under basic conditions to yield the carboxylic
acid again. Two triplets and two quartets due to the two ethyl ________
parts of the ester. One quartet further downshifted due to
closeness to oxygen, the other only slightly (close to carbonyl
oxygen). Triplets are upfield as away from the oxygens.
Nevertheless still resolved as two due to downfield shifting by
oxygen.

X: methyl propionate

Y: propanoic acid

Z: ethyl propionate
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8. Below you see the chemical structure of Rivaroxaban, an oral anticoagulant, and aspirin (incl.
parts of a synthesis).
a) Classify the two molecules as drug-like and lead-like. Explain (1 p)
b) How long does it usually take to develop a drug? (0.5 p)
c) Suppose aspirin has been deuterated and all hydrogens have been replaced with deuterium. Give
two spectroscopic methods to distinguish between deuterated and non-deuterated aspirin? Briefly
explain. (1 p)
d) Aspirin can be synthesised from salicyl alcohol in 2 steps. What are conditions a, and c and
intermediate B in the diagram below? (2 p)
[Extra point alert: e) Why do older bottles of aspirin smell like vinegar? Explain. (1 p)]

Answers

a) Rivaroxaban is an oral drug like compound according to Lipinskis rule of 5. Aspirin

is not(, but rather a lead-like compound according to Congreves rule of 3).

b) about 12 years.

c) mass spec mass difference between H and D; NMR, only odd spin/nucleon nuclei
give signal (so hydrogen but no deuterium).

d) (a) oxidation with e.g. chromic acid or KMnO4 followed by (c) esterification with
acetic acid anhydride (although acetic acid in acid conditions can be used too not very
efficient though)

e) the ester bond gets hydrolysed over time releasing acetic acid which is the smell of
vinegar.
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9. The aromatic amine aniline can be synthesised from nitrobenzene by catalytic reduction. ________
a) Assume that a synthesis of the amine was incomplete. The substrate and product have very
similar, high boiling points. How can you separate the product from the substrate? How can this be
done easily? Explain how and why. Make sure the result is the free amine (i.e. a neutral molecule).
(2 p)
b) Rationalize the magnitude and direction of the dipole moments of substrate, product and the
compound containing both functional groups, 1-amino-4-nitrobenzene (p-nitroaniline). See figure
below for direction and magnitudes of dipole moments. (2 p)
c) p-nitroaniline can be synthesised from either aniline or nitrobenzene. Which one would you
choose at a starting point and why? (1.5 p)

a) Acidify the solution of product and substrate. Then extract with an organic
solvent, e.g. ether. The amine will be protonated and stay in the aqueous phase.
The nitro group wont and will go into the ether phase. The amine salt needs to be
deprotonated with a base to yield the free amine and can be obtained by a second
extraction with an organic solvent.
b) Aniline has a free electron pair which can be donated to the aromatic ring
making it slightly more negative and the amine group positive (electron donating
group). The effect is smaller than for the next as the nitrogen has a negative
inductive effect too. In contrast the nitro group is electron withdrawing with 3
fairly electronegative elements and possible resonance structures making the ring
positive. In p-nitroaniline the two effects combine with the amine as EDG and the
nitro group as EWG.

c) start with aniline since it is o,p directing as well as activating. Nitro group would
be m-directing and deactivating.
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10. Tamoxifen is a drug that is used to prevent and treat breast cancer. Below are shown the last 3 ________
steps in one possible way to synthesis the drug.
a) Give the intermediate A and reagent b to accomplish the synthesis. (1.5 p)
b) Name the class of reaction for the first and last step shown below. (1 p)
c) Draw an energy diagram for the last reaction, i.e. the one which yields tamoxifen. Clearly
indicate substrate, product, transition state(s) and intermediate(s), if any. (2 p)
d) You want to prepare radioactive labelled tamoxifen to study the metabolism of the drug. The
half-life of the used isotope is 1 day and the total synthesis takes 3 days. With how much activity
do you have to start your synthesis to yield tamoxifen with 1000 Bq activity? (1 p)
e) When the starting compound in the tamoxifen synthesis shown here is dissolved in heavy water
(D2O) under basic conditions (OD-), some hydrogen(s) can be exchanged for deuterium. Draw the
structure of the compound after equilibration in (alkaline) heavy water. (1 p)
[Extra point alert: f) How can you explain that pure Z-isomer of tamoxifen becomes a mixture
of E and Z when exposed to too much sunlight? (1 p)]

tamoxifen

Answers:
a) A: b: PhMgBr

b) SN2, E1

c) (for H2SO4 instead of HCl)

2nd part important!!

d) 1st day synthesis double-> 2000 Bq, 2nd day double again 4000 Bq, 3rd day
again double: 8000 Bq.
e)
f) UV radiation energy from the sun can be absorbed by the double bond (and
aromatic system). When the bond gets excited the pi-bond breaks and the
molecule can rotate freely around the sigma bond, relaxation to the ground state
forms the pi bond again (in whichever orientation, E or Z). Note: a lot of UV
energy is usually required for this conversion and probably even more here due to
the conjugated system which can absorb a lot of energy.
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11. A biologically important amine derivative of glucose is N-acetylglucosamine (GlcNAc). It is an
amide between glucosamine and acetic acid. In glucosamine the 2-hydroxyl of glucose is replaced
by an amide group.
In glycosylated proteins GlcNAc is linked with its 1-hydroxyl to amino acid residue sidechains.
The bond can either be an O-glycosidic link to the hydroxyl of a serine (or threonine) or an N-
glycosidic link to an asparagine residue.
a) Draw the Haworth projection of -D-acetylglucosamine (pyranose form). (Hint: first draw the
Haworth projection of -D-glucose and then of -D-glucosamine). (2.5 p)
b) In nature the glycosylation of proteins is catalysed by enzymes. How can the hydroxyl of the
serine be activated by an enzyme for the nucleophilic attack on the C-1 of the carbohydrate? (1 p)

Answers:

a)

b) activation by a general base, e.g. a His similar to the catalytic triade in a serine
protease.
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Questions connected to the article A concise approach to substituted Quinazolin-4(3H)-one
natural products catalyzed by Iron(III) Chloride (Mekala Ramamohan, Kamaraju
Raghavendrarao, Regati Sridhar, Gudimalla Nagaraju, Kothapally Bannoath Chandrasekhar,
Sarva Jayapraksh, Tetrahedron Letters 57 (13), 14181420, 2016).
Abbreviations: Me methyl, Et ethyl, Bu butyl, Bn benzyl, DMF Dimethylformamide, 4-
Dimethylaminopyridine, THF Tetrahydrofuran, mesityllithium (2,4,6-trimethylphenyl)lithium,
amberlyst-15 ion exchange resin (strong acid!!), viz. videlicet (=namely).
(Total 10 p)

The article describes the syntheses of several Quinazolin-4(3H)-one natural products. Using an FeCl3
catalyst the products are synthesised from isatoic anhydride and amidoxime.

12. Iron (III) chloride is used as a catalyst in above described reaction.

a) Which class of compounds does this catalyst belong to? (0.5 p)
b) Name another reaction in which this compound can be used as a catalyst. (0.5 p)

a) Lewis acid.
b) E.g. EAS, chlorination
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13. Scheme 2 describes the detailed synthesis of Circumdatin H (6) from 11 and 12.
a) Using 1mmol of substrates 11 and 12 each, what is the theoretical yield of 6? What is the
experimentally achieved yield of 6 here? Give % and molar amounts. [if you cannot give exact
final numbers, describe how you can calculate it] (1 p)
b) The synthesis of 13 is achieved in two steps (i and ii). Draw the product of the first step. (1 p)
c) Carbonyl compounds can usually be directly converted into oximes using hydroxylamine. Why
can 14 not be directly reacted with hydroxylamine to yield 16? (1 p)
[Extra point alert: d) Draw a simple mechanism of the second part of the reaction from 11 and
12 to 13. (1.5 p)]

Answers:
a) theoretical yield: 100%, 1mmol
experimental yield: 80%x82%x85%x95%x95%x88%=44%; 44%*1mmol =
0.44mmol

b)

c) even though N has a higher EN than C the carbonyl carbon is less electrophilic
in an amide than a ketone since the free electron pair of the nitrogen can be
donated to the carbonyl carbon making it less electrophilic for a nucleophilic
attack from hydroxylamine.

d)
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14. Scheme 3 describes the synthesis of Bouchardatine (7) and 8-Norrutaecarpine (8) 2-cyano indole.
a) Name the class of reaction from 7 to 22. (0.5 p)
b) Give another reagent which could have been used in the reaction from 7 to 22 (Note: only
consider the reacting part and ignore the rest of the molecule)? (0.5 p)
[Extra point alert: c) Why was NaBH4 chosen in the reaction from 7 to 22? (0.5 p)
Extra point alert: d) Why is a dilute acid required in the cyclisation from 22 to 8? Can the
reaction occur if the nitrogen involved in the ring closure would be a primary amine rather than in
the Quinazolin-4(3H)-one scaffold? (1 p)]

Answers:
a) Redox-reaction, reduction.
b) Use e.g. LiAlH4 or H2 with metal catalyst.
c) Reagents mentioned in b) have issues e.g. LiAlH4 will reduce amides and
catalytic hydrogenation will reduce other double bonds (and aromatic systems)
d) A stronger, concentrated acid will protonate the nitrogen and hence eliminate
the free electron pair for a nucleophilic attack on the carbon with the hydroxyl
group. Similarly a primary amine would be easier protonated than one in the
quinazolin-4(3H)-one (aromatic, resonance structures of free electron pair =>
lower pKa).
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15. Scheme 4 describes the synthesis of Luotonin B (9) starting from cyano quinolone. Finally by ________
methoxylation Luotonin E (10) is obtained from 9.
a) Give one different way how to synthesise an ether from a primary alcohol (give the name
and/or reagents)? (1 p)
b) Give a detailed, curved-arrow mechanism for the conversion of Luotonin B to Luotonin E,
incl. all protonation and deprotonation steps and resonance structures. Note: Either show the acid
catalyzed mechanism as used here (assume H2SO4 as catalyst and not amberlyst) or the classic
base catalyzed ether synthesis! (3.5 p)
c) Which type of reaction is the methoxylation you show in b)? (0.5 p).
[Extra point alert: d) Why is the cyclisation from 25 to 9 done via the lithium intermediate and
not using the same idea as from 22 to 8 in Scheme 3? (1 p)]

Answers:

a) Williamson ether synthesis (i.e. strong base and alkylhalide), ring opening of
epoxides, etc.

b)

Alt:

c) SN2 for both.

d) The hydroxyl is required in the final methoxylation step. Using a geminal diol
(corresponding to Scheme 3) would not be very efficient as it would result in both
8 and 9 (due to the equilibrium with the aldehyde form).