Homework #1 Answer Key

Chapter 1
1) The ability of a molecule to cross the fatty cell membrane has little to do with its size, but more with
its hydrophobic character.
Oestrone is more hydrophobic than adrenaline since it has a larger carbon skeleton and only two polar
functional groups. Thus, the molecule is hydrophobic in character and can dissolve through the fatty cell
membrane.
Adrenaline has four polar functional groups and a much smaller carbon skeleton. Thus, the polar
functional groups dominate in determining the character of the molecule making it very polar and
unlikely to pass through the cell membrane.

Phenol
HO
Phenol
HO
Adrenaline

Ketone
CH O

Alcohol
OH

NHMe
Amine
Phenol
HO
Oestrone (or estrone)

There is another factor which makes it difficult for adrenaline to cross the cell membrane. In aqueous
solution, the four polar groups will be highly solvated with water molecules. In order to cross the cell
membrane, these water molecules have to be 'stripped away' and this involves an energy penalty. The
energy of desolvation for oestrone would be less since it has only two polar functional groups solvated.
3) The alkyl chains are linked to the glycerol skelton by ether linkages rather than by ester linkages.
Ethers are chemically more stable than esters to extreme conditions.

ether link
Branching

Branching

Branching

Branching

O
O

OCH2CH2NH3

O
glycerol
skeleton

ether link

The long alkyl chains are also branched, unlike those in eukaryotic cell membranes. Branching makes the
chains more resistant to oxidation.
8) The relative order of H-bonding strength is shown below
O
O

O
R

RHN

O
R

O
R

RO

Increasing strength of carbonyl oxygen as a hydrogen bond acceptor

This reflects the fact that the greater the electron density on the carbonyl oxygen, the stronger it will act
as a hydrogen bond acceptor.
The carboxylate group is the strongest hydrogen bond acceptor since a full negative charge is shared
between both oxygens.
The carbonyl oxygen of the amide will also act as a good hydrogen bond acceptor since the lone pair of
electrons on nitrogen can interact with the carbonyl group to increase electron density on the carbonyl
oxygen as shown below.

O
R

N
H

O
R

N
H

Amide - N acts as poor HBA

O acts as a good HBA

No such interaction occurs for the ketone or ester carbonyl groups, but the carbonyl groups are still
polarised resulting in the oxygen having a slightly negative charge. Consequently the carbonyl oxygen in
these functional groups can still act as a hydrogen bond acceptor, but less strongly.

9) The diagram below shows the possible intermolecular bonding interactions for the various functional
groups present in each molecule (HBA = hydrogen bond acceptor; HBD = hydrogen bond donor; vdw =
van der Waals interactions)

HBA
HBD O
H

HBD
H HBA
O

vdw
H
HBD O
HBA
Adrenaline

H3C H

HBA
CH3 O
dipole-dipole

HBD
H
N HBA
Me

CH3

CH3
H

CH3

CH3
HBD
H

O
HBA

vdw
Oestrone

HBD
H
O
HBA

vdw
Cholesterol

Notes
* It cannot be assumed that all the interactions shown actually occur.
* Adrenaline can also exist in the ionised form below, resulting in the potential interactions shown

HBD
H HBA HBD
O
H
HBA
H HBD
HBD O
N
H
Me
ionic
vdw
H
HBD O
HBA
Adrenaline

* The remainder of the carbon skeleton in each molecule has the potential to interact with other
hydrophobic molecules through van der Waals interactions. This is particularly the case for the steroid
structures.

10) Trade names are in brackets

Amoxicillin (Amoxil)
H 2N

H H
N

H
S

HO
Phenol

Me

Me

CO2H

Ranitidine (Zantac)

Me2N

CHNO2
2

N
H

NHMe

Gefitinib (Iressa)

F
HN

Cl

N
N

OMe

Atracurium (Tacrium)

MeO
MeO

OMe
N

Me

O
O
OMe

OMe

O
MeO
OMe

OMe

Chapter 2
3) Possible interactions are shown below for the side chains of serine, phenylalanine, glycine, lysine and
aspartic acid (HBA= hydrogen bond acceptor; HBD = hydrogen bond donor; vdw = van der Waals
interactions)

Serine
H2N

Glycine

Phenylalanine

CO2H

R=

O HBA
H
HBD

Amino acid
structure

vdw

No side
chain

Aspartic acid

Lysine

HBA
O

R=
HBA
H
HBD

ionic
H
HBD

HBD

O
HBA
H
HBD

Aspartate
HBA
O
ionic

O
HBA

H
H HBD
HBD

5)
The structure of L-alanyl-L-valine is shown below.

H 2N

O
N

CH3

CO2H

An attempt to couple alanine directly to valine may well produce the desired product but a whole range
of other structures will also be formed.

H2 N

CO2H

CH3

H2N

H3C

CO2H

H2N

CH3

O
N

CH3

+ many other peptides

CO2H

For example, L-valyl-L-alanine is an equally likely product. There is also nothing to stop alanine coupling
with itself, or valine coupling with itself to form L-alanyl-L-alanine and L-valyl-L-valine respectively.
Furthermore, there is no reason why any of the above dipetides that are formed could not undergo a
further coupling reaction to form tripeptides, tetrapeptides etc.
The reaction is also likely to need forcing conditions since one is attempting to form an amide between
an amine and a carboxylic acid which are more likely to form a salt at room temperature. Forcing
conditions are likely to result in racemisation of asymmetric centres.
Due to these problems, it is necessary to protect the amino group of one amino acid and the carboxylic
acid of the other before a coupling reaction is attempted. It is also important to have coupling reagents
(e.g. dicyclohexylcarbodiimide) in order to achieve milder, non-racemising conditions.
6) The functional groups involved are alcohols and phenols. Both of these functional groups can form
hydrogen bonds. When the groups are phosphorylated, the phosphate groups are ionised and will
interact with ionic groups rather than hydrogen bonding groups.

H2N

H
R

Serine

CO2H

Tyrosine

Threonine

R=
HBA O

HBD H
alcohol

H HBD

alcohol

Phosphorylation

phenol

Phosphorylation

Phosphorylation

O
O
O

HBD
H
O
HBA

CH3 HBA

P
O

O
CH3

O
Ionic

The tertiary structure will alter as a result (see section 5.2.6).

Ionic

O
Ionic

O
P