IMPORTANT INSERT, READ THIS FIRST
This year's final examination deals with the chemistry of AZT, a drug used in the
treatment of AIDS. This insert contains constants and information on AZT. A second
insert contains the periodic table. You may use the reverse, blank sides for scratch work
but enter all work to be graded in the spaced provided with each question.
The examination contains two parts:
1) the lab examination with two equally weighted questions that will test your ability
to apply principles learned in the lab to the experimental characterization of AZT.
The score from this portion will be used to determine the lab portion of your final
grade.
2) a lecture examination with 9 questions that will test your ability to apply chemical
principles to the understanding of AZT’s chemistry. The score from this portion
will be used to determine the lecture portion of your grade.
The drug AZT (C10H13N5O4), marketed as Zidovudine by Glaxo, is a potent inhibitor of
the viral enzyme reverse transcriptase. Its covalent structure is given below. The
molecule consists of two rings: a RNA/DNA base (Thymine in this case) and a
deoxyribose sugar. AZT is identical with the DNA nucleoside deoxythymidine except
that an –OH group on the ribose ring has been replaced with an azide group, -N3. AZT
has a normal melting point of 121ºC.
Useful Fundamental Constants
R = 8.3144 J/K-mole
NA = 6.022 x 1023 molecules/mole
kB = 1.3807 x 10-23 J/K-molecule
c = 2.9979 x 108 m/s
h = 6.626 x 10-34 J-s
m(electron) = 9.109 x 10-31 Kg
Kw = 1.00 x 10-14 at 25.00ºC
1 eV = 96.484 kJ/mole
Covalent Structure of AZT
(With the exception of the methyl (CH3) group, the hydrogen atoms bonded to the
carbons are not shown.)
N3
O
HN
OH
N
O
CH3
O
NAME:__________________________________
READ THE INSERT FIRST
Lab-1) Although AZT is a useful drug, it has serious side effects. A physician must
closely monitor its concentration in the blood of a patient receiving treatment. Blood
contains many diverse compounds. Suggest an analytical method for AZT that is
selective, sensitive, and practical. Provide the basis for the selectivity and sensitivity.
Lab-2) The state of protonation of AZT affects its potency as an inhibitor and modeling
of its pharmacology requires knowledge of its pKa. AZT is normally delivered as the
uncharged form and not as the conjugate base, an anion. Outline an experimental
protocol that would yield the pKa.
Lec-1) (20 points) Cervoni et al. employed calorimetry to determine the binding of AZT
to the enzyme nucleoside diphosphate (NDP). Their data yielded the following results at
20.0ºC: the binding constant, K, for the binding reaction AZT + NDP = AZT-NDP,
K = 1.1 x 103; the standard enthalpy change for the reaction, ΔHº = 13.8 kJ/mole. From
these results, calculate the following quantities:
a) ΔSº, the standard entropy change for the binding reaction. Interpret the result.
b) the value of the binding constant K at 30.0ºC
Lec-2) (15 points) The azide group attached to the ribose ring is responsible for AZT’s
inhibitory properties. Draw acceptable Lewis-dot structures of a model compound,
methyl azide (H3CNNN). Provide the formal charges on each heavy atom. Consider the
possibility of resonance and provide all acceptable structures if more than one structure is
possible. Methyl azide readily decomposes to form molecular nitrogen. If more than one
structure is possible, which one is supported by this chemical fact?
Lec-3) (25 points) This question deals with the three-dimensional structure of AZT which
is used in the design of better reverse transcriptase inhibitors.
a) Given AZT’s covalent structure, what is the hybridization of the two nitrogen
atoms in the Thymine ring?
b) All the heavy atoms in the Thymine ring lie in the same plane. What is the origin
of this striking planarity?
c) What hybridization for the nitrogen atoms in the Thymine ring is implied by the
planarity of the ring?
d) The CCN bond angles about the N covalently bonded to the ribose ring are
119.28º, 120.50º, and 120.20º. Discuss how these data indicate the planarity of
the Thymine ring and support (or refute) your answer to part c.
e) The ribose ring, in contrast, to the Thymine ring is non-planar and is found in the
solid state and the solution phase to exhibit a variety of three-dimensional
structures. Briefly discuss the basis for this striking difference.
Lec-4) (20 points) In aqueous solution, AZT is present as the uncharged form whose
structure is given on the insert. This is the acid form. The conjugate base, an anion, is
formed by removal of the proton from the protonated nitrogen in the Thymine ring, and
The pKa of AZT was determined by Balon et al. to be 9.45 at 25ºC.
a) Calculate under physiological conditions, i.e. pH 7.20, the fraction of the drug
present in the uncharged acid form.
b) Calculate the value of pKb for the conjugate base at 25ºC.
Lec-5 (10 points) Could one form a platinum(II) complex of AZT? If this is possible,
suggest a stoichiometry for the complex and reaction conditions that one would employ
to prepare the complex.
Lec-6) (25 points) Pomona Professor Emeritus Corwin Hansch has developed a powerful
quantitative method for relating the molecular properties of drugs to their biological
activity. Novak and Kovač investigated the electronic properties of AZT to provide
parameters for a Hansch equation. To this end, they used the photoelectric effect to
determine the ionization energy of AZT.
a) In their experiment, they used the radiation from a helium plasma with a
wavelength of 58.5 nm to ionize gaseous AZT and showed that the liberated
electron had a speed of 2.06 x 106 m/s. Calculate from these data the ionization
energy of AZT in kJ/mole and eV.
b) If one use Spartan with a 3-21G* basis set, one calculates -8.99 eV for the orbital
energy of the HOMO. Obtain a "computational" value for the ionization energy.
How well do the computational and experimental results compare?
c) The HOMO of AZT has  symmetry and is localized on the heavy atoms of the
Thymine ring. Which atomic orbitals are used to construct the HOMO? Will an
electron in the HOMO ever be found at the nucleus? Briefly explain.
d) The absorption of longer wavelength UV (ultraviolet) light excites the electrons.
The longest wavelength of light with this property is at 266 nm. Is AZT colored?
Lec-7) (18 points) J. F. Arenas et al. studied the thermal decomposition of methyl azide
(CH3N3) in which it forms one mole of molecular nitrogen. They found that the
decomposition exhibits first order kinetics and that at 495 and 505 K, the first order rate
constants are 8.74 x 10-6 1/s and 2.09 x 10-5 1/s, respectively. The first step in the
reaction appears to be rate determining.
a) Suppose in an experiment that a flask is filled with methyl azide at a partial
pressure of 20.0 torr. Calculate the time required at 495 K for the concentration
of methyl azide to diminish to 5.00 torr.
b) From the data provided above, calculate the energy of activation for the reaction.
c) Calculate at 495 K, the average kinetic energy per mole due to translation. Atomic
weights in g/mole: H, 1.00; C, 12.0; N, 14.0.
c) The data cited above yield an entropy of activation of 12 J/K-mole. Given this
datum and all the other information on azides provided in this examination,
propose a structure for the activated complex of the first, rate-determining
elementary step in the reaction. What are the products of this first step?
Lec-8) (15 points) Handlon and Oppenheimer reported that thiols (compounds such as
CH3CH2SH that have an -SH group) can reduce the azide group(-N3) in AZT to an amino
(-NH2) group. This reaction is relevant to the lifetime of AZT in the blood. They studied
the kinetics of this reaction and the following data can be extracted from their paper.
initial concentrations
[CH3CH2SH] (M)
[AZT] (M)
0.100
0.100
0.200
0.100
0.0500
0.200
initial reaction rate
(M/s)
6.35 x 10-8
1.27 x 10-7
6.35 x 10-8
a) Determine the rate law for the reaction.
b) Determine the rate constant.
c) Suppose that the reaction is run under conditions in which the initial concentrations
of CH3CH2SH and AZT are 0.100 M and 0.0010 M, respectively. A simple
function of the concentration of either CH3CH2SH or AZT will yield a straight
line when plotted versus time. Which compound? Which function?
Lec-9) (2 points) The synthesis of AZT requires a soluble salt of the azide anion.
Suggest a soluble, inexpensive salt.