Ab initio Hartree–Fock/6-31G** calculation on 9-β-D-arabinofuranosyladenine-5′-monophosphate molecule: Application to the analysis of its IR and Raman spectra

Ab Initio Hartree–Fock/6-31G** Calculation on 9-�-D-Arabinofuranosyladenine-5�-Monophosphate Molecule:Application to the Analysis of Its IR and Raman Spectra

BELEN HERNANDEZ,1 RAQUEL NAVARRO,1 ANTONIO HERNANZ,1 GERARD VERGOTEN2

1 Departamento de Ciencias y Tecnicas Fisicoquımicas, Universidad Nacional de Educacion a Distancia (UNED), Sendadel Rey s/n, E-28040 Madrid, Spain

2 CRESIMM, Universite des Sciences et Technologies de Lille I, UFR de Chimie, Bat. C8, 1er et,59655 Villeneuve d’Ascq Cedex, France

Received 25 May 2001; revised 12 November 2001; accepted 3 January 2002Published online 18 July 2002 in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/bip.10140

ABSTRACT: 9-�-D-Arabinofuranosyaldenine-5�-monophosphate (5�-ara-AMP) is an ar-abinonucleotide that has antiviral and antitumor activity. The accurate knowledge ofthe nature of its vibrational modes is a valuable step for the forthcoming elucidation ofdrug–nucleotide and drug–enzyme interactions. The FTIR and FT Raman spectra(4000–30 cm�1) of 5�ara-AMP and two deuterated derivatives ara-AMP-dC8 (deutera-tion in C8) and ara-AMP-d7 (deuteration in C8, amino and hydroxyl groups) arereported. Theoretical vibrational calculations were performed using the Hartree–Fock/6-31G** method. An assignment of the observed spectra is proposed considering thescaled potential energy distribution of the vibrational modes of the 5�ara-AMP moleculeand the observed band shifts by deuteration. The scaled ab initio frequencies are ingood agreement with the experimental data (�3 cm�1 SD). © 2002 Wiley Periodicals, Inc.Biopolymers (Biospectroscopy) 67: 440–455, 2002

Keywords: ab initio Hartree–Fock/6-31G** calculation; 9-�-D-arabinofuranosyalde-nine-5�-monophosphate; IR and Raman spectra

INTRODUCTION

Many of the chemicals that are currently used asantiviral and anticancer chemotherapeutics be-long to the class of nucleoside and nucleotide an-alogues. The family of arabinosides has attracteda great deal of attention because of their broadspectrum of antiviral and antitumor activities.

9-�-D-Arabinofuranosyaldenine-5�-monophos-phate (5�-ara-AMP, Fig. 1) is a first generationarabinonucleotide showing a parallel activity to

those of ara-A nucleoside, but exhibiting a greatersolubility in water. This fact makes it easier touse in therapy. Moreover, 5�-ara-AMP is consid-ered to be less toxic and less immunosuppressivethan the nucleoside. Also, its half-life in humanserum is prolonged with respect to ara-A.1 Thecompound is an inhibitor of hepatitis B virus(HBV) replication in vitro and in vivo in the duckmodel of infection,2 as well as being active againstDNA viruses of the herpes group.3–7 5�-ara-AMPis an effective chemotherapeutic agent4,8–11 thatis used in combination with inhibitors of adeno-sine deaminase.4,9 The compound is curativeagainst L 1210 leukemia in mice12 and for severaltypes of mammalian tumors.13 The mechanism ofits activity involves the phosphorylation of thismonophosphate of ara-A by cellular kinases to the

Correspondence to: R. Navarro ([email protected]).Contract grant sponsor: MEC (Spain) DGES Project; con-

tract grant number: PB96-0149.Biopolymers (Biospectroscopy), Vol. 67, 440–455 (2002)© 2002 Wiley Periodicals, Inc.

440

active 5�-triphosphate,9,14 which was proved toinhibit the viral DNA polymerase in competitionwith d-adenosine triphosphate.3,15

The IR and Raman spectra of the ara-A mole-cule and their proposed assignment according toab initio Hartree–Fock (HF)/3-21G calculationswere reported.16 In the present work, we extendthe study to ara-A-5�-monophosphate. We presentthe vibrational analysis of 5�-ara-AMP and twodeuterium derivatives synthesized for this pur-pose. The assignment is based on the normal co-ordinate treatment performed using the ab initioHF/6-31G** method.

The vibrational spectra for some related mole-cules17–37 were reported. The assignments wereproposed considering the information provided bytheoretical calculations, which were mainly abinitio. Higher level methods [Møller–Plesset(MP) calculations] were applied mainly to baseresidues.30,32,38,39 Density functional theory (DFT)methods were used for calculations on bases,40,41

and they have begun to be applied to vibrationalcalculations on nucleosides.33,42 Pioneering struc-tural studies on a whole nucleotide were performedwith DFT.43 In order to elucidate nucleotide–druginteractions by vibrational spectroscopy, a series ofcalculations on a family of nucleoside and nucleo-tide analogues is being performed, which in thisway tests the higher level available methods (HF/6-31G** and DFT44,45) on this type of molecules.

MATERIALS AND METHODS

Materials and Instrumentation

Adenine 5�-ara-AMP was purchased from SigmaChemical Co. and used without further purifica-

tion. The 5�-ara-AMP-d7 isotopomer (deuterationat C8, amino, and hydroxyl groups) was synthe-sized by heating a diluted solution of 5�-ara-AMPin deuterium oxide at 80°C for 20 h, followed byrecrystallization and freeze-drying. The secondisotopomer, 5�-ara-AMP-dC8 (deuteration at C8

position), was then obtained from 5�-ara-AMP-d7

by solving the former isotopomer in H2O and sub-sequent recrystallization and freeze-drying proce-dures. The degree of exchange at the C8 position,which was higher than 90%, was verified by 1H-NMR spectroscopy.

The FTIR spectra of 5�-ara-AMP, 5�-ara-AMP-d7, and 5�-ara-AMP-dC8 (Fig. 2) were recorded ina Bomem-DA3 interferometer while working un-der a vacuum (�133.3-Pa pressure). For the me-dium IR (MIR) region, the spectra of the polycrys-talline compounds in KBr pellets were recordedusing a DTGS/MIR detector with a Globar sourceand KBr beamsplitter and coadding 500 interfero-grams. The value of the effective apodized resolu-tion (s) was 0.89 cm�1 (RES � 1.0 and Hammingapodizing function).

Far IR (FIR) spectra from 700 to 200 and from200 to 40 cm�1 of 5�-ara-AMP, 5�-ara-AMP-d7,and 5�-ara-AMP-dC8 in polyethylene pellets wererecorded by coadding 1000 interferograms (s� 1.77 cm�1, RES � 2, and Hamming apodizingfunction) using a DTGS/FIR detector and a high-pressure mercury lamp. Mylar beamsplitters of 3and 12 �m were used for the former and the latterFIR regions, respectively.

The FT Raman spectra of the three compounds(Fig. 3) were recorded using the Raman accessoryof the Bomem-DA3 interferometer. A Kryptondischarge lamp, pumped Nd3�:YAG laser (work-ing at 1064 nm as the exciting source), a quartzbeamsplitter, and an IGA detector working at 77K (cooled by liquid N2) were used. The Ramanemission was collected at 180° backscattering ge-ometry. One hundred interferograms were coad-ded to obtain each spectrum with a nominal res-olution of 8 cm�1 after Blackman–Harrisapodization. A parallel series of FT Raman spec-tra was recorded with the IGA detector at roomtemperature to obtain a better S/N ratio in the3500–2000 cm�1 interval.46

The second derivatives of all the recorded spec-tra (Savitzky–Golay algorithm47) were calculatedto resolve the bands containing more than onecomponent and thus to help in the assignment ofthe experimental spectra.

Figure 1. The 5�-ara-AMP molecule.

HF/6-31G** CALCULATION OF 5�ARA-AMP MOLECULE 441

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442 HERNANDEZ ET AL.

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Normal Coordinate Treatment

The quantum mechanical calculations were car-ried out using Gaussian 9448 running on an IBMRisc 6000-3CT computer platform. Postprocess-ing of the vibrational modes was made on thebasis of the Wilson GF method49 using the Re-

dong program.50 This program allows the conver-sion of the FX matrix (Cartesian force constants)into FR (force constants as defined on the molec-ular internal coordinates, Tables I and II), theredundancy treatment, and the scaling of theforce constants.

Table I. Internal Coordinates Definition Used in the Treatment of the Results from Ab Initio HF/6-31G**Vibrational Calculation on 5�-ara-AMP Molecule

1 �POO33 38 �C�5OH 75�C�3OC�4OC�5 112 �C5B (C5OC6N1N6)2 �POO35 39 �C�5OH� 76 �N9OC�1OO�4 113 �N7A (N7OC4C5C6)3 �PAO36 40 �O�5OPAO36 77 �C�3OC�4OO�4 114 �N7B (N7ON9C8H)4 �O33H 41 �O�5OPOO35 78 �O�4OC�1OC�2 115 �C8 (C8OC4N9C�1)5 �O35H 42 �O�5OPOO33 79 �C�5OC�4OO4 116 �N9A (N9ON7C8H)6 �C2ON3 43 �O36APOO33 80 �C�1OC�2OO�2 117 �N9B (N9ON3C4C5)7 �C6ON1 44 �O36APOO35 81 �C�2OC�3OO�3 118 �C�1 (C�1ON1N9C8)8 �N3OC4 45 �O33OPOO35 82 �C�3OC�2OO�2 119 �N6 (N6ON1C5C6)9 �N1OC2 46 �POO35OH 83 �C�4OC�3OO�3 120 �HOC2 (HOC2N1N3)

10 �C5OC6 47 �POO33OH 84 �C�4OC�5OO�5 121 �HOC8 (HOC8N9N7)11 �C5OC4 48 �N1OC2ON3 85 �C�4OO�4OC�1 122 �N1OC2

12 �C8ON7 49 �N3OC4ON9 86 �C�1OC�2OH 123 �C2ON3

13 �N7OC5 50 �N9OC8ON7 87 �C�3OC�2OH 124 �N3OC4

14 �C4ON9 51 �C2ON3OC4 88 �C�2OC�3OH 125 �N1OC6

15 �N9OC8 52 �C6ON1OC2 89 �C�4OC�3OH 126 �C6ON6

16 �C6ON6 53 �C4ON9OC8 90 �C�3OC�4OH 127 �C5ON7

17 �C�1OC�2 54 �C8ON7OC5 91 �C�5OC�4OH 128 �N7OC8

18 �C�2OC�3 55 �C4ON9OC�1 92 �C�2OC�1OH 129 �C8ON9

19 �C�3OC�4 56 �C�1ON9OC8 93 �C�4OC�5OH 130 �N9OC4

20 �C�4OC�5 57 �N7OC5OC4 94 �C�4OC�5OH� 131 �N9OC�121 �N9OC�1 58 �N3OC4OC5 95 �O�2OC�2OH 132 �C4OC5

22 �C�4OO�4 59 �C5OC6ON1 96 �O�3OC�3OH 133 �C5OC6

23 �C�1OO�4 60 �C5OC4ON9 97 �O�5OC�5OH 134 �C�1OC�224 �C�2OO�2 61 �N7OC5OC6 98 �O�5OC�5OH� 135 �C�2OC�325 �C�3OO�3 62 �C5OC6ON6 99 �O�4OC�4OH 136 �C�3OC�426 �C�5OO�5 63 �N9OC�1OC�2 100 �O�4OC�1OH 137 �C�4OC�527 �N6OH 64 �N1OC2OH 101 �C�3OO�3OH 138 �C�4OO�428 �N6OH� 65 �N3OC2OH 102 �C�2OO�2OH 139 �C�1OO�429 �C2OH 66 �N7OC8OH 103 �POO�5OC�5 140 �C�2OO�230 �C8OH 67 �N9OC8OH 104 �HOC�5OH� 141 �C�3OO�331 �O�2OH 68 �N9OC�1OH 105 �N1A (N1OC5C6N6) 142 �C�5OO�532 �O�3OH 69 �C6ON6OH 106 �N1B (N1ON3C2H) 143 �O5OP33 �O�5OP 70 �C6ON6OH� 107 �N3A (N3ON1C2H) 144 �POO33

34 �C�1OH 71 �HON6OH� 108 �N3B (N3OC5OC4N9) 145 �POO35

35 �C�2OH 72 �C4OC5OC6 109 �C4A (C4OC5C6N7)36 �C�3OH 73 �C�1OC�2OC�3 110 �C4B (C4C8N9C�1)37 �C�4OH 74 �C�2OC�3OC�4 111 �C5A (C5ON3C4N9)

�, stretch; �, bend; �, out-of-plane bend; �, torsion.

Table II. Symmetry Coordinates Definition for NH2 Group

NH2 scissoring (2 � �HON6OH�) � �C6ON6OH � �C6ON6OH�NH2 rocking �C6ON6OH � � C6ON6OH�

�HON6OH� � �C6ON6OH � �C6ON6OH�


The structural parameters and vibrational nor-mal modes of the 5�-ara-AMP molecule were cal-culated using the ab initio HF/6-31G** basis set.A full geometry optimization was carried out. Thestarting geometry was a model built by addingthe phosphate residue to the O�5 position of theara-A structure obtained by X-ray diffraction.51 Avibrational calculation using the same basis set(HF/6-31G**) was carried out on the 5�-ara-AMPoptimized geometry.

RESULTS

Geometry Optimization

The optimized ab initio geometry is shown inFigure 4. The arabinose ring presents a reason-able degree of pucker (Table III), similar to those

found by X-ray diffraction for ara-A. This type ofpuckering is 3T4 for the model (crystalline struc-ture of ara-A) and 3T2 for the optimized one; bothNorth conformations C�3-endo are very common inarabinosides. The conformation over the exocyclicbond C�4OC�5 is gauche-trans in the model and inthe optimized geometry. Base-sugar relative ori-entation is in the anti range. The N9OC8 andC�1OC�4 bonds are nearly eclipsed in the optimizedstructure. The base ring structure is completelyplanar, but the amino protons present a slightdisplacement from this plane.

Amino Protons of Adenine Base

The dihedral angles HON6OC6ON1 andH�ON6OC6ON1 of some nucleosides and nucleo-tides containing the adenine base are shown in

Figure 4. The 5�-ara-AMP molecule. There are two perspectives of the model (basedon ara-A X-ray diffraction data) and the ab initio HF/6-31G** optimized structures.


Table IV. The structures obtained with the HF/3-21G basis set present a planar geometry for theamino group. The optimized geometry for 5�-ara-AMP (present work, HF/6-31G** basis set) pre-sents a slight distortion from the planarity. Sim-ilarly, some ab initio second-order MP (MP2) andHF/6-31G* studies on different base residuesfound an energy minimum with nonplanar aminogroups,52,53 a structure more stable (1 kcal mol�1

for adenine) than the planar geometry. The avail-

able data from X-ray diffraction (ara-A and 5�-dAMP51,54) reveal the existence of distortions inthe amino groups, showing nontotally planarstructures, but with hydrogen atoms slightly de-viated up and down the ring base plane. In thecase of ara-A, according to the crystal structure,only one of the protons is involved in a hydrogenbond. In the crystal lattice of 5�-dAMP both pro-tons seems to be involved in the hydrogen bonds,but one of them seems to be very weak. It is

Table III Comparison of Conformational Parameters of 5�-ara-AMP Molecule: Model Geometry and Ab InitioHF/6-31G** Optimized Structure

Parameters Model Ab Initio Structure

Exocyclic torsion angles�(O�4OC�1ON9OC8) 57.82° (anti) �3.31° (anti)(O�4OC�1ON9OC4) �108.43° �170.76°(O�5OC�5OC�4OC�3) �177.45° (gauchetrans) �178.57° (gauchetrans)O�5OC�5OC�4OO�4 65.79° 64.35°�(C�5OC�4OC�3OO�3) 81.56° 84.66°

Phosphate group�(POO�5OC�5OC�4) 180.0° �155.61°C�5OO�5OPOO �180.0° �55.30°C�5OO�5OPOO1 60.0° �178.34°C�5OO�5OPOO3 60.0° 70.58°

Endocyclic torsion angles�0(C�4OO�4OC�1OC�2) �4.38° 6.04°�1(O�4OC�1OC�2OC�3) �19.00° �26.36°�2(C�1OC�2OC�3OC�4) 33.53° 35.25°�3(C�2OC�3OC�4OO�4) �36.97° �32.65°�4(C�3OC�4OO�4OC�1) 26.17° 16.97°Pa 25.18° 9.05°�max

b 37.05° 35.69°Sugar pucker 3T4

3T2

The model was built adding a phosphate group in the 5�-position to the X-ray diffraction structure of ara-A nucleoside. Themodel geometry was from ara-A X-Ray diffraction Data.

a tgP ��4 �1� � ��3 �0�

2�2 �sen 36° sen 72°�.b �max � �2/cos P.

Table IV. Dihedral Angles HON6OC6ON1 (a) and H�ON6OC6ON1 (b) of Adenine Amino Groups and C6ON6

Bond Lengths in 5�-dAMP, ara-A, and 5�-ara-AMP

Molecule

X-Ray Ab Initio HF/3-21G

Angle (°)C6ON6

(Å)

Angle (°)C6ON6

(Å)a b a b

5�-dAMP �162.6 28.7 1.321 179.5 �0.6 1.345ara-A 173.0 �10.1 1.350 179.2 0.6 1.3385�-ara-AMP — — — 177.0a 3.0a 1.338a

a The data are from X-ray diffraction and ab initio optimized structures HF/6-31G**.


reasonable to attribute the observed distortions tothe crystalline package.

Normal Coordinate Analysis

The vibrational calculation was carried out on theoptimized structure at the HF/6-31G** level, us-ing the same set of base functions. The resultingvibrational force field was scaled considering allthe available information: theoretical, experimen-tal, and bibliographical. The scale factors (SFs)that affect the force constants of the internal co-ordinates were varied in each scaling cycle. Aftereach change of SFs, the corresponding potentialenergy distribution (PED) was calculated andthen its consistency with the experimental infor-mation was checked.

The results of the calculation, once scaled,show an excellent numerical fit to the experimen-tal data. The average deviation between thescaled frequencies and the experimental ones (Ta-

ble V) is 2.8 cm�1 (4.0 cm�1 SD). The most fre-quent range of values of the SFs, grouped by typeof internal coordinate, are shown in Table VI. Thefinal PED confirms the previously published re-sults for related molecules.

DISCUSSION

The experimental and scaled theoretical frequen-cies, as well as the PED, are presented in TableVII. The FTIR and FT Raman spectra of 5�-ara-AMP and its deuterated derivatives are shown inFigures 2 and 3, respectively. The assignment ofthe observed bands is discussed by spectral re-gions according to the nature of the normalmodes.

3600–2500 cm�1 Spectral Region

The region from 3600 to 3300 cm�1 is quite diffi-cult to resolve. In the IR spectrum the bandsappear overlapped and a very broad, complex,and strong band is observed (Fig. 2). The FT Ra-man spectrum carried out with the IGA detectorat 298 K provides more information. At 3470cm�1 a broad band with medium to weak inten-sity appears. This band is assigned to the sym-metric stretch of the amino group. Fitting thisvalue, the calculation predicts the antisymmetricstretch, �a (NH2), at 3589 cm�1.

The bands at 3332 (3325 cm�1 in Raman) and3278 cm�1 (3280 cm�1, strong in Raman) areassigned to the O�3OH and O�2OH stretches (bycomparison with other nucleosides and nucleo-tides16,37,44,45,55,56), while those that appear at3250 (very strong in IR) and 3225 cm�1 (resolvedby the second derivative) are attributed to the twoOOH groups of the phosphate group. Calcula-tions predict that these bands should shift by

Table V. Statistics on Numerical Fitting betweenExperimental and Theoretical Frequencies afterScaling Process

5�-ara-AMP HF/6-31G**

N 82Vibrational normal modes 105��scal � �exp� � 0 371 � ��scal � �exp� � 10 3810 � ��scal � �exp� � 20 5��scal � �exp� 20 —

�i�1

n

��scal � �exp�

n 2.8Standard deviation 3.98

N, the number of experimental frequencies; differences��scal � �exp� are in cm�1.

Table VI. Scaling Factors (SF), Grouped by Type of Normal Coordinate, Used in Scaling of Ab Initio ForceConstants of 5�-ara-AMP

Stretching (�) Bending (�) OPB (�) Torsion SF (�)

5�-ara-AMP SF (�):1–0.8 All SF (�) 1–0.7 SF (�): 1–0.7 SF (�): 0.97–0.7HF/6-31G** �OH*0.6–0.65 �C5

0.6–0.65

�C�2O�2

0.6–0.65�CC, �CN (im)0.7 �N7 �C�1C�2�CO�4A0.65 �N9 �C�2C�3�PAOA0.6 �HOC2 �C6N6

�POO�5A0.64


Table VII. Observed and Calculated (Scaled Ab Initio HF/6-31G**) Wavenumbers for 5�-ara-AMP Molecule

IR � (cm�1) Raman �� (cm�1)

Scaled Ab Initio

� (cm�1) PED

vb 3589 50 �N6H� � 48 �N6H (�aNH2)Overlapped 3470 m 3470 43 �N6H� � 55�N6H (�sNH2)3332 2nd dv 3325 2nd dv [�90] 3332 100 �O�3H3278 vs 3280 s [�893] 3278 100 �O�2H3250 vs Overlap [�885] 3250 100 �O33H3225 2nd dv Overlap [�878] 3225 100 �O35H3132 w 3129 s [�832] 3132 99 �C8H3067 w 3067 m 3064 99 �C2H2980 vvw 2979 s 2992 51 �C�5H� � 49 �C�5H� (vaC�5H2)2956 2957 s 2941 51 �C�5H� � 49 �C�5H� (�sC�5H2)2910 vw 2910 s 2910 92 �C�1H— 2894 2nd dv 2897 51�C�4H, 41 C�3H— 2887 2nd dv 2887 54 �C�3H,45 �C�4H— — 2752 91 �C�2H1696 vs 1696 w 1696 39 �C6N6, 38 �NH2scissors, 8 �C5C6, 5 �C5C6N1

1662 2nd dv 1658 w 1662 18 �N3C4, 16 �C5C6, 15�C6N1, 12 �C2N3, 11 �N1C2,9�C5C6N6, 5 �NH2 scissors, 5 �NH2 rock

1611 m–s 1611 m 1611 18 �NH2 scissors, 14�N1C2, 14 �C6N1, 11�C4C5, 10 �C2N3

1556 m 1556 s 1537 33 �C6N6, 12 �NH2 scissors, 11 �N3C4, 6�C2N3, 5 �C5C6,4 �C5C6N1

1513 m 1513 s 1513 15 �C8N7, 12�N9C�1H, 9 �N9C8H, 6 �N7C8H, 6 �N9C8

1477 m 1475 s 1477 46 �N9C�1H, 12 �C�2C�1H�, 8 �C8N7, 6 �O�4C�4H�, 5 �N9C�1,4�N9C8H

1458 w 1458 sh–m 1458 14 �C�4C�5, 11 �C4C�5H, 9 �O�2C�2H, 9 �C5C�4H, 8 �O�5C�5H,8 �O�3C�3H, 7 �C�1C�2H, 4 �C�4C�5H, 4 � O�5C�5H�

1427 m 1426a 2nd dv 1427 20 �C4N9, 19 �C8N7, 9�N1C2, 6 �C4C5, 5 �N7C5C4, 4 �C6N6

1411 sh w Overlapped 1411 70 �H�C�5H, 7 �O�5C�5H, 5�C�4C�5H1401 w 1404 vs 1387 18 �C�2O�2H, 7 �N1C2, 7 �O�4C�4H, 6 �C�1C�2, 6�C�2C�1H,

6 �C6N1

1359 b m 1360 vw 1360 15 �C6N1, 10�C2N3, 9�N7C5, 9�O�4C�4H, 5 �C�4C�5H1352 2nd dv 1347 w 1346 17 �O�4C�4H,11 �C�5C�4H, 6�C�4C�5H, 5 �O�5C�5H, 5 �O�2C�2H,

5 �C�1C�2H, 4 �C�2C�3H1324 m 1325 vs 1325 22 �N3C2H, 19 �N1C2H, 6 �C5C6, 6 �C5C4, 5 �C4N9,

4 �C6N1

1316 m 1313 overlap 1312 20 �C�3C�4H, 19 �C�3O�3H, 7 �N1C2H, 4 �C�5C�4H, 4 �O�5C�5H,4 �O�4C�4H

1293 vvw 1295 sh w 1298 20�C2N3, 12 �N3C4, 10 �O�4C�4H, 8 �C6N1, 6 �N1C2,5 �C5C6, 5 NH2 rock, 4 �N9C�1

1285 vw 1287 m 1286 13 �N7C8H, 13 �O�4C�4H, 9�N9C8, 6 �C4C5, 6 �C8N7,5 �N9C8H, 5 �N7C5, 3 �C4N9

1266 sh 1266 sh 1265 26 �O�5C�5H, 15�O�5C�5H�, 14 �O�4C�4H, 13 �C�4C�5H,11�C�4C�5H�, 5 �C�4C�5

1252 sh 1252 w 1244 11 �N9C�1, 11 (�N7C8H � �N9C8H), 8 �N7C5, 7 �C6N1,7 NH2 rock, 6 �C4N9, 6 �C�3O�3H, 5 �C�1C�2H

1238 b overlap 1238 22 �C�2O�2H, 18 �C�3O�3H, 12�C�1C�2H, 5 �C�3C�2H1212 vs 1216 w–m 1213 25 �C�4C�3H, 11 �C�2C�3H, 10 �C�3O�3H, 8 �O�5C�5H, 7�C�2O�21197 m 1198 w 1198 14 �N7C8H, 16 �N9C8H, 8 �N9CI�, 8 NH2 rock, 7 �N7C5,

4 �C8N7

1176 s 1172 m 1184 18 �C�3O�3, 15 �C�4C�5, 11 �C�2O�2, 6 �C�5O�5, 5 �C�2C�3C�41160 2nd dv 1162 m 1160 35 �C�3O�3, 16 �C�2O�2, 9 �C�2C�3, 4 �C�4C�5

Table VII continues


Table VII. Continued


Scaled Ab Initio

� (cm�1) PED

1132 1130 1132 14 �C�5O�5, 10 �C�2C�3, 8 �PAO36, 7 �C�3O�3, 6 �C�2O�2H,5 �C�2C�3H

1127 1127 1129 46 �PAO36, 7 �PO33, 6 �PO35, 6 �PO33H, 5 �O33PO35

1105 m 1106 w 1096 17 �C�5O�5, 6 �C�4C�5, 6 �C�1C�2, 6 �N9C�1, 5 �O�4C�1, 4�C�3C�41084 s 1084 w 1084 17 �C�3C�4, 14 �C�3O�3H, 6 �C�3O�3, 6 �N9C�11059 vs 1059 26 �C�4O�4, 12�C�3O�3, 7 �C�4C�5H, 6 �C�2O�2, 6 �O�5C�5H,

5 �C�4C�5, 5 �C�4C�5H, 4 �C�1O�41053 2nd dv 1057 b 1050 10 �C�4C�5, 9 �C�3O�3H, 8 �C�2C�3, 7�C�4C�5, 6 �C�3C�4H,

4 �C�4C�5H1035s 1034 m 1025 34 �C�1O�4, 8 �C�1C�2, 6 �C�2O�2, 5 �N9C8

1026 vs 1032 36 �POO33, 27 �POO35, 21 �POO33H1012 2nd dv 1015 sh 1017 42 NH2 rock, 21 �N3C4, 6 �O�4C�1, 4�C6N1

Overlapped 1004 m 1004 76 �PO35H, 7 �PAO36, 7 �PO33

983 vw 983 shvw 979 10 �C�1C�2, 9 �C�1C�2O�2, 7�C�1O�4, 7 �C�1C�2H, 6 �C8N7C5,5 �C8N7, 4 �C�2C�3O�3, 3�N3C4

962 vs 965 vvw 962 53 �POO33H, 24 �POO33, 12 �POO35, 6 �PAO36

949 m 950 m 951 25 �HAC2, 25�N3A, 24 �N1B, 12 �C2N3, 10 �N1 C2

919 vs 922 vw 914 12 �C�1OC�2, 12 �POO35H, 9�C�3C�4, 7�C�2C�3, 4 �C�4C�5,4 �PO35

895 899 894 19 �N1C2N3, 15 �C2N3C4, 15 �C6N1C2, 8 �N7C5

885 886838 m 838 s 834 11 �N7C8, 10�N7B, 10 �N9C8, 9�C�4O�4, 8�HOC8, 8�N9A.792 s 792 vs 792 12 �POO�5, 6�N7A, 4 �N1C2, 4�N9C�1C�2, 4 �C2N3, 4�N3B

784 sh 778b w 770 47 �POO�5, 6 �C�4C�5O�5, 4�C�5O�5, 4 �POO36

729 s 724 21 �N1C2, 9 �N7C5,7�C5C6,6�C4N9, 5 �N9C8, 5 �C6N1C2,4�C6N6,4 �C4C5

708 s 707 b w 700 23 �N9C�1, 6 �C�4O�4C�1, 6 �C5C6, 4 �C�1C�2, 4 �C6N1C2,4 �C8N7C5, 4 �N1C2N3

680 b w 680 b w 672 13�N3B, 12�N6, 12�C5B, II 6�N1A, 8�N1C2, 6�C5A, 6�N9B

648 w–m 648 b w 635 11 �N7C8, 4 �N1C2, 4 �N9C�1C�2, 4 �C�4O�4C�1, 4 �C�3C�4O�4,3 �C�1C�2O�2, 3 �C5C6, 3 �C�1N9C8, 3 �C5N7

618 w 618 w 618 13 �N9C�1O�4, 9 �C6N1C2, 8 �N3C4C5, 5 �C�2C�1O�4, 5�C�4O�4C�1,5 �C4C5C6, 4 �N1C2N3, 4 �C5C4N9, 3 �C�1C�2

Overlapped 602 w 591 16 �C5C6N6, 7NH2 rock, 6 �N3C4N9, 6 �C�3C�2O�2,5 �C�2C�3C�4, 5 �C�4C�5O�5, 4 �N7C5C6, 4 �C5C6

580 w–m 581 b w 578 7 �C�4C�3O�3, 6 �C5C6N6, 5 �C�2O�2, 5 �C�4C�5O�5, 4 �C�3C�4,4 �C�3C�2O�2, 4 �C�3O�3

561 w 561 w–m 563 20 �C2N3, 13 �N1C2, 6 �N3C4, 5 �N7C8, 5�C4B, 4�C8,3 �N6, 3�C5B, 3 �N7A

531 w 534 sh w 531 18 �C5C6N6, 14 �C5C6N1, 5�C�1C�2O�2, 5�C2N3C4,4 �C�5C�4O�4, 4 �C4C5C6, 4 �C�5C�4O�4, 4�N7C5C6

520 w–m 524 w–m 516 21 �C5C6N1, 9 �C2N3C4, 6�C6N1C2, 6 �C�1C�2O�2, 4�N3C4N9,3 �C�5C�4O�4

502a m 505a w–m 503 12 �PO�5C�5, 10�O�5PO33, 9 �O36APO35, 7 �C�3C�4C�5,6 �O33PO35, 5 �O�5PAO36 5 �C�4C�3O�3, 5 �C�3C�2O�2

471 vw 473w 471 25 �O�5PAO36, 20 �O33PO35, 8 �O36APO35, 6 �O�5PO33

414 w 417 m 412 75 �C�2O2

388 m 379 14 �C�5C�4O�4, 10 �C�2O�2, 10 �C�3O�3, 8 �C�2C�3O�3, 6�O�4C�1,4 �C�4C�5

357 w–m 360 m 364 19 �O�5PO33, 17�O36APO33, 12 �C�3O�3, 8 �C�2C�3O�3, 7 �PO35,6�O36APO35, 5 �PO�5C�5

Table VII continues

2nd dv 2nd dv

sh w sh m


deuteration to 2424, 2385, 2360, and 2346 cm�1,respectively. Several of these wavenumbers arefound in the spectra of the isotopomers, such as2424 (Raman), 2340 (IR), and 2346 cm�1 (Ra-man).

The two �C8H and �C2H CH stretches of thebase16,17,19,22,28,56 appear at 3132 (3129 cm�1,strong in Raman) and 3067 cm�1. The COHstretches from the sugar moiety are observed atlower wavenumbers between 2990 and 2750cm�1. The �C8O

2H2 is calculated at 2998 cm�1

and it appears overlapped in the spectra of thedeuterated derivatives.


In this range we find the bands arising from inplane vibrations of both the base and the sugarmoieties.16,20,21,24,26,56,57 The scissoring vibra-tion of the amino group appears in this re-gion16,17,19 –21,24,26,57 and contributes signifi-cantly, according to the HF/6-31G** ab initiotreatment, to the modes giving rise to the bandsat 1696 (very strong in IR and weak in Raman,35% contribution), 1611 (medium intensity in IRand Raman, 14% contribution), and 1556 cm�1

(medium intensity in IR and strong in Raman,11% contribution). In these three cases the scis-

Table VII. Continued


Scaled Ab Initio

� (cm�1) PED

342 343 sh 344 23 �O33PO35, 21 �O�5PO35, 14 �O�5PAO36, 12 �C�3O�3,337 338 m 7 �O36APO33, 6 �PO33, 4 �C�5C�4O�4297 w 297 w 308 17 �C5C6N6, 8 �C�2O�2, 8 �N9C1O�4, 4 �C6N1, 4 �N1C2

278 w 280vvw 284 17 �N9C�1, 15 �N9C�1O�4, 13 �C�1C�2O�2, 5 �C5C6N6,4 �C4N9, 4 �O�4C�1

267vvw 268 16 �C�3C�2O�2, 15 �C�4C�3O�3, 6 �C�3O�3, 5 �C�1C�2O�2238 sh vw 230 46 �POO35, 7 �PO�5C�5, 5 �C�3C�4C�5224 w 228 b vw 224 23 �N9C�1, 8 �N3C4, 7 �N9C�1C�2, 6 �N7A, 4 �C5C6N6

191 m 192 22 �POO33, 9 �O33PO35, 8 �POO35, 8�C�4C�5O�5,4 �PO�5,4 �O�5PO33, 4 �PO�5C�5, 4�C�4C�5

179 m 179 50 �POO33, 14 �O33PO35, 7 �O�5PAO36, 6 �O36APO33

163 w 165 vvw 163 9 �C�1C�2, 7 �O�4C�1, 6 �C4N9C�1, 4 �C2B, 4 �N9C�1C�24�PO�5C�5

153 s Crystal modeOverlapped 143 w 143 13 �O�4C�1, 10 �C4N9C�1, 9 �C5C6, 6 �O�4C�4, 6 �C�1N9C8,

5 �C�1C�2, 5 �N1C6

115 m 107 12 �POO33, 11 �POO�5, 9 �C�4C�5, 9 �C�4C�5O�5, 7�C�3C�4C5,�, 7 �C�5C�4O�4, 5 �O33PO35, 5 �O�5PAO36,4 �O�5PO35

101 vw 103 vvw Crystal mode93 w–m Crystal mode81 m 86 19 �C�3C�4, 16 �C�2C�3, 12 PO�5C�5, 7 �C�1C�2, 6 �C�4C�5,

5�C�4C�574 m Crystal mode62 m 65 24 �C�1C�2, 17 �O�4C�1, 11 �O�2C�2, 5�C4B, 4 �C�2C�3,

4 �PO�5C�559 sh 58 46 �N9C�1, 11 �PO�5, 5 �C�2O�2, 4 �C�4C�5

43 bw 40 28 �C1�C�2, 22 �O4C1�, 8 �N9C�1, 6 �C�2C�3, 4 �C4B

27 23 �O�4C�1, 14 �O�4C�4, 8 �N9C�1, 10 �C�5O�5, 6 �C�2O�222 46 �PO�5, 18 �C�4C�5, 6 �PO33

11 26 �C�5O�5, 19 �O�4C�1, 12 �C�4O�4, 8 �C�3C�4, 6 �C�1C�2

Proposed assignment and potential energy distribution (PED) of the vibrational normal modes Types of vibration: �, stretching;�, in plane bending; �, out of plane bending; �, torsion. Intensities: vs, very strong; s, strong; m, medium; w, weak; vw, very weak;b, broad, sh, shoulder; 2nd dv, second derivative. Observed isotopic shifts are in brackets.

a Doublet center.

2nd dv


soring vibration is coupled with stretching mo-tions of the CC and CN bonds, mainly of thepyrimidine fragment of the base.17,21 These basestretches give rise to the IR band at 1662 cm�1,along with a total contribution of the order of 10%from the amino group. This group of IR bands of5�-ara-AMP and its deuterated derivatives is de-tailed in Figure 2.

The second derivative of the spectra revealsthat there are several components under the pro-file of these bands. Comparing the spectra of thethree studied compounds containing the adenineresidue16,44 (Fig. 5), relative changes in frequencyand intensity of the bands are observed. A possi-ble interpretation of these differences would bedifferent crystalline packing in each case and,consequently, different intermolecular interac-tions among the molecules in the crystal. Thecoupling among dipoles of different moleculeswould also be responsible for the observed split-ting.21

The bands of the free acid (5�-ara-AMP in Fig.5) appear at higher frequency (1696 cm�1) thanthe bands of the sodium salts of the nucleotides(5�-dAMP, 1640 cm�1); this was observed in

similar compounds. The possible protonation ofN1 and the changes that this process introducesinto the �-electronic structure of the base rings,58

bond orders, and force constants could explain theobserved shifts. Studies of the protonated bases insolution show that when the adenine is proton-ated at the N1 position,59,60 the correspondingRaman band appears at 1696 cm�1, a result sim-ilar to that observed here for 5�-ara-AMP. Thepossible shifts undergone on bending vibrationsappearing in this range and due to the formationof hydrogen bonds should also be considered. Asimilar argument was used to explain the abnor-mally high frequency (1670 cm�1) of these bandsin the spectrum of solid adenine.59

The FTIR spectra of 5�-ara-AMP dissolved in2H2O are compared with the spectra of the solidand its 5�-ara-AMP-d7 and 5�-ara-AMP-dC8 isoto-pomers in Figure 6. As may be seen, in the 5�-ara-AMP-d7 spectrum a band centered on 1696 cm�1

still appears, which is less intense and broader

Figure 5. A comparison of the IR spectra in the solidstate of 5�-dAMP, ara-A, and 5�-ara-AMP in the spec-tral region of 1750–1550 cm�1 (recorded in absorbanceunits).

Figure 6. The FT Raman (A) and FTIR (spectrum B,absorbance) spectra of 5�-ara-AMP, the FTIR absor-bance spectra of its deuterated derivatives 5�-ara-AMP-d7 (C) and 5�-ara-AMP-dC8 (D), and the FTIR absor-bance spectrum of 5�-ara-AMP in 2H2O (0.05 moldm�3; E).


than in the spectrum of 5�-ara-AMP, which has abroad shoulder at 1654 cm�1. The relative inten-sity of the shoulder is greater in 5�-ara-AMP-d7than in 5�-ara-AMP. On the other hand, in the IRspectrum of the deuterated derivative 5�-ara-AMP-dC8, the shoulder has the same relative in-tensity as in 5�-ara-AMP. Contributions from thedifferent CC and CN stretches of the pyrimidinering to these modes (Table VII) justify the factthat they do not disappear with deuteration in theamino group. Nevertheless, changes are inducedbecause of the shift of the scissoring vibration ofthe amino group to lower frequencies. The deu-teration practiced in the 5�-ara-AMP-d7 deriva-tive also affects the N6 atom, but more weakly,and the internal coordinates in which N6 partici-pates. These coordinates contribute to the modesgiving rise to the bands between 1696 and 1662cm�1. The greater intensity of the shoulder at1654 cm�1 in the spectrum of 5�-ara-AMP-d7could be due to a frequency shift of these coordi-nates that involve the most immediate environ-ment of N(6)H2 (see in Table VII the compositionof the normal mode that gives rise to the bands at1696 and 1662 cm�1) as a result of the isotopicsubstitution. This effect is not present when deu-teration is only at C8, as in the case of 5�-ara-AMP-dC8.

A single band at 1625 cm�1 appears in thespectrum of the 5�-ara-AMP solution (Fig. 6). Thisband is narrower than the corresponding band ofthe solid, and it is located at the same frequencyobserved for ara-A and 5�-dAMP. This band ischaracteristic of adenine and corresponds to ringstretches55,61 decoupled from the scissoring vibra-tion. The rigidity of the solid favors the existenceof strong intermolecular couplings,61 which giverise to broad and split bands. In solution theinteractions are weaker than in the crystallinesolid, which leads to sharper signals.

It is important to emphasize that the presenceof the bending vibration of H2O (1660 cm�1) inthis spectral region can also contribute to varia-tions in the relative intensity of some of the sig-nals discussed here (especially the shoulder at1654 cm�1). This observation indicates small dif-ferences in the water content of the differentproducts.

The bands at 1513 (medium intensity in IR andstrong in Raman) and 1477 cm�1 (1475 cm�1

strong in Raman) are attributable to vibrations ofthe imidazole ring,17,21 which also include theparticipation of the glycoside bond, and a contri-bution from sugar vibrations in the case of the

band at 1477 cm�1. The former is shifted to 1486(1488 cm�1 in Raman) by deuteration at C8; in thelatter, the deuteration effect is not so clear. In thespectra of the deuterated derivatives, a broadband appears that makes the detection of newsignals more difficult. Nevertheless, according tothe proposed assignment, only a small shift isexpected. Vibrations of the imidazole ring alsogive rise to a band at 1427 cm�1, which is inagreement with the previous results for adeno-sine.21

The band at 1458 cm�1 is assigned to thesugar moiety, as well as the one that appears at1411 cm�1, which is attributed to the scissoringvibration of the C�5H2 methylene25,58,62 coupledwith other sugar bends. In the Raman spectrumthis band overlaps with the more intense one at1405 cm�1, which corresponds to a rather delo-calized mode, with participation from almostthe whole molecule. Tsuboi et al.35 recently pro-posed a new assignment for the HOC�5OH� scis-soring in thymidine, locating this vibration at1481 cm�1. Nevertheless, our results for 5�-ara-AMP at the HF/6-31G** level and for othernucleotides and nucleosides16,37,44,45 are consis-tent with their previous assignment.25,58,63 TheIR band at 1360 cm�1 also shows significantcontributions from both the sugar and base moi-eties, the latter being somewhat more impor-tant. Toyama et al. in their work on adenosine21

assigned the band at 1376 cm�1 to a highlydelocalized mode with participation from al-most the whole molecule, a description veryclose to that suggested by the ab initio calcula-tion for this region. The intensity of the banddecreases sharply after deuteration and it isshifted to 1350 cm�1. In the 5�-ara-AMP-dC8derivative it has a slightly higher intensity.

The band at 1325 cm�1 in the Raman spectrumis assigned to vibrations of the pyrimidine ring,which include an in plane bend of C2OH17,64 withsmall contributions from the imidazole ring. It issimilar to that found for the ara-A molecule.16

The band (weak in IR and Raman) at 1293 cm�1

is also due to pyrimidine ring vibrations; the Ra-man band that appears at 1287 cm�1 is originatedalmost exclusively by the imidazole ring, togetherwith small contributions from the sugar. Thisband is displaced by deuteration at the C8 posi-tion.

The weak band at 1252 cm�1 is sensitive toisotopic substitutions21 at 1,3-15N2 and 2-13C anddeuteration at C8. The calculation predicts contri-butions for the base that include in plane C8OH


bend and a small participation from the sugar.This in plane C8OH bend shows its maximumcontribution21 at 1198 cm�1, according to the cal-culation. The stretch of the glycoside bond con-tributes to the bands at 1252 and 1198 cm�1 with11 and 7%, respectively. The bands at 1352, 1266,1238, 1212, and 1160 cm�1 are due to practicallypure vibrations of the sugar.12


The PAO stretch of the phosphate group repre-sents the most important contribution (46%) tothe band at 1127 cm�1. The remaining POOstretches also participate in the normal mode thatoriginates this band, although to a lesser ex-tent.54,65 This band overlaps with the one at 1132cm�1 (1130 cm�1 in Raman), which is mainly dueto the CC and CO stretches of the sugar. ThePAO stretch also contributes to the correspond-ing normal mode (8%). Similarly, the bands at1026 (very strong in IR), 1004, and 962 cm�1 areassigned to the phosphate group, the latter bandbeing very strong in IR. In solution, at a slightlybasic pH, the phosphate group is in the totallydeprotonated form, ROO�5O(PO3)2�. In the IRspectra of 5�-ara-AMP in 2H2O, two bands, char-acteristic of the PO3

2� group, appear: one band isbroad and overlapped with the stretching bandsof the sugar CO, centered on 1086 cm�1 (asym-metric stretch, �as PO3

2�), and the other band,corresponding to the symmetric �s PO3

2� stretch,is at 977 cm�1.

The IR bands at 1132, 1105, 1084, and 1059cm�1 are due to practically pure vibrations of thesugar fragment,21 mainly CO stretches and lessimportant contributions from CC stretches. Otherauthors33,35 found similar results for differentnucleosides in this spectral region.

The band at 1012 cm�1 has a relevant contri-bution (42%) from the amino rocking vibra-tion.19,26 This band does not appear in the IRspectrum in solution. It is expected that the bandshifts by deuteration on 5�-ara-AMP-d7. However,the presence of a large complex signal in thisregion covering the range of 1290–990 cm�1

makes it impossible to confirm this point.At 949 cm�1 a band appears that is due to out

of plane vibrations of the pyrimidine ring, includ-ing the �C2OH out of plane bends (25%), which isin agreement with previous results for relatedmolecules.17,19,21 The �C8OH out of plane bends,the �C8N7 and �C8N9 torsions, and other out of

plane bends of the imidazole fragment give rise tothe IR band at 838 cm�1.17,19

The band at 919 cm�1 is due to sugar vibra-tions (mainly CC stretches) that are coupled withvibrations of the phosphate group. The POO�5bond stretching contributes to the bands at 784(47%)64 and 792 cm�1 (8%), the latter beingmainly due to out of plane bends of the base, inagreement with the results for adenosine.21

At 729 cm�1 a strong Raman band appears,which is attributed to different CC and CNstretches of the base. This signal may correspondto the so-called “base breathing” vibration. Theband at 708 cm�1 (strong in IR) presents a highcontribution from the stretch of the glycosidebond coupled with different stretches and bendsof both the base and the sugar.

The band at 680 cm�1 is due to out of planebends of the base, which include that correspond-ing to the amino group,21 �N6. The band at 648cm�1 arises from different torsions of the base(the highest contribution corresponds to the�C8N7 torsion17) and different bends in the neigh-borhood of the glycoside bond. This type of bendincludes at least one of the two atoms C�1 andN9. Similar contributions are found for the nor-mal mode that originates the band at 618 cm�1.The �C2N3 torsion and other out of plane vibra-tions of the base17 give rise to the weak band at563 cm�1.

Vibrations with dominant contributions fromthe base, mainly in plane bends, contribute to thebands that appear at 524 and 297 cm�1. In planeand out of plane vibrations of the base and theglycoside bond contribute to the mode that givesrise to the band at 224 cm�1.

Mixed base-sugar modes originate the bands at591, 531, 278 (involving the glycoside bond), 163,and 143 cm�1. Dominant contributions from thesugar appear at 580, 412 (C�2OO�2 torsion), 379,268, 81, and 74 cm�1. Several bends of the phos-phate group65 give rise to the band at 502 cm�1.The second derivatives reveal that this bandsplits, possibly because of molecular interactionslike dipolar coupling. The same effect is observedin the band at 357 cm�1, which could also be dueto the phosphate polar group. Practically purevibrations of the sugar give rise to the bands at580, 388, 268, and 163 cm�1. The torsions of thePOO bonds contribute to the bands at 191, 179,115, and 59 cm�1. The �N9C�1 torsion is predictedby the ab initio method at 58 cm�1.


CONCLUSIONS

The experimental vibrational spectra of the 5�-ara-AMP molecule were assigned. The wavenum-bers obtained from the scaled ab initio HF/6-31G** calculation are in excellent agreementwith the observed wavenumbers in most cases(4.00 cm�1 SD) and with previous results fromrelated molecules or fragments.

A remarkable feature of the 5�-ara-AMP opti-mized geometry is the nonplanar structure of theprotons in the amino group. Previous works pro-posed planar amino structures. Our results agreewith other studies on the cytosine39 base.

The authors wish to thank the DGES Project ofthe MEC (Spain) for their financial support. Thecomplete scaled ab initio HF/6-31G** force field inGaussian 94 Fx format may be obtained from theauthors on request.

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