142
M.M. Glice et al./Journal of Molecular Structure 450 (1998) 141–153
d-form and S(−) or l-form. The dextrorotatory R(+)
enantiomer is of pharmacological particular interest
because it inhibits aromatase 2–3 times more strongly
than the racemate and about 10–30 times more
strongly than the levorotatory S(−) enantiomer [7,11].
AG is a polar molecule and has a dipole moment of
2.83 D (in dioxane at 30ЊC) [11]. It can interact with
the surrounding molecules primarily via a moderate-
strength hydrogen bond network. AG is virtually
insoluble in water, but is freely soluble in chloroform,
methanol and many organic solvents. It can be crystal-
lized in two polymorphic forms [12]. In the elemen-
tary cell a pair of AG molecules forms a double
centrosymmetric hydrogen bond.
An AG methanol–water solution has pH of 6.2–7.3
that may result from the simultaneous presence of a
weakly acidic imide NH moiety and a basic phenyl-
amino group. The latter group is probably responsible
for the formation of a hydrochloride salt (CAS 31075-
85-1).
The IR spectrum of AG in Nujol mull was tenta-
tively assigned in 1961 [13]. The present work reveals
that in high frequency spectral regions the assignment
must be corrected owing to intermolecular interactions
not considered carefully enough in the earlier studies.
In the present paper we focus on the vibrational
spectra of AG immersed in a series of solvents of
variable polarity and different proton donor–acceptor
properties. The concentration-dependent spectra were
studied with particular emphasis on the possible
formation of hydrogen-bonded species. The results
may shed more light on the details of the AG inter-
molecular interactions with the receptor site located
on aromatase backbones.
(0.718 g, 0.0051 mol) in toluene (10 ml) was added
dropwise and the mixture was refluxed for 6 h. The
inorganic precipitate was filtered off and the filtrate
was evaporated. The oily residue was purified by SiO2
chromatography (CHCl3) and the product was crystal-
lized from ethyl acetate. Yield: 0.107 g (10%).
The solutions of N-deuterated derivative of AG and
GT were prepared by dissolving the appropriate
amount of sample (AG or GT) in 5 ml of CDCl3,
adding 1 ml of D2O and shaking for 1 h. Next, the
CDCl3 layer was dried by adding 1 g of anhydrous
sodium sulfate and used directly for IR and Raman
measurements.
The IR spectra were recorded on a Perkin-Elmer
FT-IR 1725X spectrometer. Solid samples were
measured in KBr pellets. The IR spectra of the solu-
tions (in CCl4, CHCl3, CDCl3, CH3CN) were
measured in KBr cuvettes with variable path length
(0.044–0.91 mm) depending on the concentration of
the sample. A spectral resolution of 4 cm−1 was used.
The Raman spectra were recorded on a Perkin-
Elmer FT-IR 2000 system equipped with a Raman
accessory using a diode-pumped Nd:YAG laser
(1064 nm) as an excitation source. Solid samples
and the solutions (in CCl4, CHCl3, CDCl3, CH3CN)
were measured in capillary tube. For most diluted
solutions a fluorescence cuvette was used for the
measurements to maximize the Raman signal. A spec-
tral resolution of 4 cm−1 was used.
The low temperature Ar matrices were prepared by
depositing the sample and Ar gas on the cold tip of the
cryostat [Displex closed cycle refrigerator (APD
Cryogenics Inc.)] maintained at 12 K.
2.2. Theoretical chemistry
2. Methods
The ab initio restricted Hartree–Fock (RHF)
method with the standard Gaussian basis sets (6-
31G**, 6-31G*, 3-21G) implemented in the Gaussian
94 code [14] was used. The Berny algorithm was
employed for the optimization of molecular geometry
expressed in terms of the bond lengths, valence bond
angles and tetrahedral angles. Standard convergence
criteria were used to terminate the geometry opti-
mization process. The normal modes of molecular
vibrations were calculated with the use of the analytical
second derivatives of the total molecular energy, with
respect to the nuclear displacements, for the optimal
2.1. Experimental
The AG samples were obtained from the production
unit of the Pharmaceutical Research Institute Warsaw.
N-Methylglutethimide was obtained via the fol-
lowing condensation procedure. A mixture of GT
(1 g, 0.0046 mol), finely powdered potassium hydro-
xide (0.55 g), potassium carbonate (1.90 g) and 18-
crown-6 (20 mg) in toluene (25 ml) was stirred and
refluxed for 15 min. Then a solution of iodomethane