MEDICINAL CHEMISTRY 2019-20 ASSESSED COURSEWORK WORKSHEET 2
Your mark for this piece of work will constitute 50% to your final coursework mark for the
module. Complete all the following questions as instructed and submit with answers to the
sulphonamide worksheet 1 to Blackboard by the deadline 2pm Friday 3rd April 2020.
Instructions: The following questions relate to the synthesis and metabolism of lidocaine and
its derivatives. Answer ALL questions on these pages in pen by ticking by using a purple
font to highlight in bold your correct answer to each question. Any answer not clearly
given will not be marked. Maximum marks are shown in brackets for each part.
1 Do not answer this question.
Submit both the IR spectra from your practical work, each clearly labelled and
identifying the peak due to the amide carbonyl group. On the back of each spectrum
give the relevant weight of product and a full calculation of percentage yield, and give
the melting point range for the intermediate.
(10)
Answer ALL the following, clearly marking the correct answers to each of questions 2,
3 and 5-7, and completing the answers to questions 4 and 7-9.
2. Why would ethanol be a poor choice of a solvent for the reaction between 2,6-
dimethylaniline and -chloroacetyl chloride in stage 1 of your synthesis of lidocaine?
a) It reacts with the primary amine group of dimethylaniline.
b) The product will react with ethanol.
c) It reacts with the alkyl chloride group of -chloroacetyl chloride.
d) It reacts with the acyl chloride group of -chloroacetyl chloride.
(1)
3. In stage 1 of your synthesis of lidocaine, which one is true of the reaction between the
primary amine group of 2,6-dimethylaniline and -chloroacetyl chloride?
a) The acyl carbon is less electrophilic than the alkyl carbon so reacts preferentially.
b) The acyl carbon is more electrophilic than the alkyl carbon so reacts preferentially.
c) The primary amine is too electrophilic to react with the alkyl carbon.
d) The acyl and alkyl carbons are equally reactive.
1
(1)
4. A diagram is not required. Using an appropriate diagram, explain whychloroacetyl
chloride doesn’t attack -chloro-2,6-dimethylacetanilide in stage 1 of your synthesis of
lidocaine.
chloroacetyl chloride cannot attack -chloro-2,6-dimethylacetanilide during synthesis
because it is not a very strong nucleophile. There is therefore a nucleophilic
substitution at the carbon atom in chloroacetyl chloride, as there is more nucleophilic
reactivity. Sterically it is more likely for a nucleophile to attack the carbon on the
carbonyl group (in chloroacetyl chloride), rather than the other way around, due to
the molecules’ spatial arrangements.
(3)
5. In stage 2 of your synthesis of lidocaine, which one best explains why hydrochloric acid
protonates the nitrogen atom of the diethylamine group of lidocaine preferentially to that
of the amido group?
a) The amide nitrogen is protected by the two methyl groups of the aromatic ring.
b) The diethylamine nitrogen has a lower pKa than the amide nitrogen.
c) The two ethyl groups are electron withdrawing.
d) The amide nitrogen has a lower pKa than the diethylamine nitrogen.
(1)
6. Correctly identify whether each of the following statements about local anaesthetic
agents is true (T) or false (F).
a) The amide nitrogen must always be adjacent to the aromatic ring. F
b) A secondary or tertiary amine is an essential part of the pharmacophore for local
anaesthesia. F
c) The –CH2- between amide and amine can be extended to –C2H4-. T
d) With the exception of the steric shield and amide chain, the aromatic ring must not be
further substituted. T
(4)
2
7. Give both the chemical name and chemical formula of the by-product that is washed
away at the sink in step 2 of your synthesis of lidocaine.
(2)
C4H12ClN (diethylammonium chloride)
8. For each of the following steps(a)-(c) in the metabolic pathway of lidocaine, correctly
name the biochemical process occurring and identifying whether it is a phase I or phase
II process.
Phase I:
oxidative
dealkylation
Phase I:
hydrolysis
Phase I:
oxidation
(Me=CH3)
(3)
9. Illegal doping of horses by administration of lidocaine can be detected by analysis of
urine for the metabolite, 3-hydroxylidocaine. This compound can be made synthetically,
as shown below, for use as a standard in the analytical method.
(i) A mechanism need not be drawn. Give the two reagents required to carry out step
a), and draw a mechanism for this step.
HNO3 and NaOH
(4)
3
(ii) In step a), why does the nitro group add to the ring adjacent to the methyl group?
CH3 is an ortho, para directing group, meaning it donates electrons, and therefore the
electrophile (NO2+) joins adjacent to it. This means it can withdraw said electrons, and
become stabilised.
(1)
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