molecular structure of an isocytosine analog: combined x-ray structural and computational study of...

Structural Chemistry, Vol. 10, No. 4, 1999

Molecular Structure of an Isocytosine Analog: CombinedX-ray Structural and Computational Study of2-Diethylamino-6-methyl-5-w-propyl-4(3H)-pyrimidinone

Liliana Craciun,1,2,4 Radu Custelcean,1,3 and Sorin Mager1

Received January 4, 1999; accepted March 2, 1999

The structure of 2-diethylamino-6-methyl-5-n-propyl-4(3H)-pyrimidinone has been studied byX-ray crystallography and quantum-chemical calculations. X-ray analysis established that 2-di-ethylamino-6-methyl-5-«-propyl-4(3H)-pyrimidinone exists exclusively as the lactam tautomerprotonated at the N3 ring nitrogen in the solid state. Crystals of 2-diethylamino-6-methyl-5-n-propyl-4(3H)-pyrimidinone are monoclinic (space group P21/n); the unit-cell dimensions are: a= 11.0460(8) A, b = 5.0064(4) A, c = 22.8358(17) A, a = 7 = 90°, 0 = 90.521(1)°. In thecrystal, molecules of 2-diethylamino-6-methyl-5-n-propyl-4(3H)-pyrimidinone are assembled inplanar centrosymmetric dimers by strong resonance-assisted N—H . . .O intermolecular hydrogenbonds from the NH group of one molecule to the C=O of the adjacent molecule (N—H . . .Odistance 2.804 A). Bond distances and angles are generally similar to those reported forthe corresponding tautomer of isocytosine and derivatives. Quantum-chemical calculations on2-diethylamino-6-methyl-5-rt-propyl-4(3H)-pyrimidinone are also reported in order to estimate therelative energies of the possible tautomeric forms; ab initio and DFT results predict the coexistenceof the N3 and AH tautomers in the gas phase. There is excellent correspondence between thecrystal and the HF/6-311G** or B3LYP/6-31G* calculated structures of the N3 lactam form; thelargest deviations between the experimental and computed structures are mostly the effects of strongintermolecular H bonds in the crystal.

INTRODUCTION

Prototropic tautomerism of heterocyclic compoundshas been studied since the early years of this century. Agreat number of papers on this subject have appeared andare reviewed in [1-4]. In particular, the tautomerism ofpyrimidine and purine bases has been extensively inves-

1 Department of Organic Chemistry, 11 Arany Janos Str., "Babe§-Bolyai" University, 3400 Cluj-Napoca, Romania.

2 Department of Chemistry, Princeton University, Princeton, New Jer-sey 08544-1009.

3 Department of Chemistry, Michigan State University, East Lansing,Michigan 48824-1322.

4 Correspondence should be addressed to Dr. Liliana Craciun, Depart-ment of Chemistry, Princeton University, Frick Laboratory, Princeton,New Jersey 08544-1009; e-mail: [email protected]

tigated both experimentally and more recently, quantum-chemically, as they are constituents of nucleic acids andmany other compounds of biological significance [5].Tautomerism and H bonding are mutually dependent andmay change considerably depending on the environment.

The H-bonding properties of nucleic bases direct the

fidelity of DNA replication and transcription processes inmolecular biology and are of major relevance to muta-genesis because of their role in mispairing and occur-

rence of rare tautomeric forms [5b, 6]. By studyingnucleic base analogs, it may be possible to furtheran understanding of their origins and the mechanismsresponsible for spontaneous and induced mutations.

The investigation of the less common nucleic base,2-amino-4-pyrimidinone (isocytosine), is justified by its

3031040-0400/99/0800-0303$ 16.00/0 © 1999 Plenum Publishing Corporation

KEY WORDS: 2-Diethylamino-6-methyl-5-n-propyl-4(3H)-pyrimidinone; tautomerism; X-ray crystal structure;ab initio and DFT calculations.

304 Craciun, Custelcean, and Mager

Fig. 1. 2-Diethylamino-6-methyl-5-n-propyl-4(3H)-pyrimidinone and some structurally related 4-pyrimidinones.

structural relationship to the canonic bases, cytosine andguanine (Fig. 1). Isocytosine designates the pyrimidinepart of guanine, and even though it is not involveddirectly as a carrier of the genetic code, it is of biologi-cal significance and its medical applications are numer-ous [7]. A variety of 2-amino-4-pyrimidinones displayanticancer, antiviral, or antibacterial properties [8], orare rendered as valuable agrochemicals [9]; specifically,platinum group metal complexes of isocytosine andderivatives attracted considerable attention because oftheir antitumor activity [10]. In addition, the isocytosinering system has been explored as a molecular function-ality for supramolecular assembly of H-bonded rod andlayered organic materials [11], as a host for guests withsuitable H-bonding abilities [12], or as color reagents formetal cations [13].

In the course of our studies on 2-amino-4-pyrimidi-nones and related compounds, we have synthesized sev-eral novel isocytosine derivatives that exhibit high toxic-ity and have tested them as potential herbicides, care-fully examining their tautomerism in various media toestablish the prevailing tautomeric structure, and ulti-mately, the H-bonding and preferred coordination sites[9a-b, 14]. In this paper we present the X-ray crys-tallographic study combined with theoretical ab ini-tio and density functional theory (DFT) calculations

of an isocytosine analog, 2-diethylamino-6-methyl-5-n-propyl-4(3H)-pyrimidinone. The relative stabilities ofthe three possible tautomeric forms of 2-diethylamino-6-methyl-5-n-propyl-4(3H)-pyrimidinone, amino-oxo Nlor N3, and amino-hydroxy AH (Fig. 2), are calcu-lated and compared to experimental data. This struc-tural information adds to the 2-amino-4-pyrimidinonedatabase and may eventually allow the derivation ofimproved, more detailed, and more generally applicablecorrelations between isomerism, structural relaxation,and biological consequences, assessed through compar-ative functional assays.

RESULTS AND DISCUSSION

X-ray Crystal Structure of 2-DiethyIamino-6-methyl-5-n-propyl-4(3H)-pyrimidlnone

2-Diethylamino-6-methyl-5-n-propyl-4(3H)-pyrimi-dinone may occur, in principle, in three distinct tau-tomeric forms corresponding to different protonationsites: at the ring nitrogen atoms (the cycloamidic or lac-tam tautomers, N1 and N3), and at the exocyclic oxygenatom (the enol tautomer, AH) (Fig. 2). In previous work,we suggested that 2-diethylamino-6-methyl-5-n-propyl-

Fig. 2. Tautomeric forms of 2-diethylamino-6-methyl-5-n-propyl-4(3H)-pyrimidinone.

Molecular Structure of an Isocytosine Analog 305

4(3H)-pyrimidinone along with the 5-ethyl- and 5-n-butyl- analogs exist predominantly as the 4(3H)-lactamtautomers (N3) in solution and in the solid state [14b].The molecular structure of 2-diethylamino-6-methyl-5-n-propyl-4(3H)-pyrimidinone, as determined by X-raycrystallography in this study, establishes that it existssolely as the N3 tautomer in the solid state, confirmingour earlier prediction.

The 2-amino-4-pyrimidinone moiety appears inmany synthetic or naturally occurring compounds exclu-sively in the amino-oxo tautomeric forms, and no otherforms (imino, hydroxy) were detected except in non-polar environments (gas phase, nonpolar matrices). Themolecular structure of isocytosine itself was of interestbecause it shows the existence of the two lactam tau-tomers, Nl and N3, in the same crystal [15], hydrogenbonded to one another to give base pairs in a manneranalogous to the purine-pyrimidine pairing proposed byWatson and Crick for the structure of DNA [6a]. The for-mation of H-bonded dimers is a common feature for iso-cytosine derivatives, whether the dimer is formed fromone molecule of each of the two lactam forms [15, 16]or from the same tautomer [8c, 11]. Interestingly, twodistinct crystal structures were reported for 6-methyliso-cytosine: one in which the N1 tautomer occurs exclu-sively in the crystal forming pairs linked by N—H . . .Nhydrogen bonds [17], and the other one very similar tothat reported for isocytosine, where both the N1 and N3tautomers are present in the crystal lattice [11]. Sev-eral crystal structures of various metal complexes ofisocytosine and derivatives were reported; such studies,aimed to identify the coordination mode of the nucleo-base and its specific interactions with the metal, identi-fied the N3 atom of the ring as the preferred coordinationsite, although metal binding of the exocyclic NH2 or COgroups has also been described [18]. These previouslyreported crystal structures of isocytosine and derivativesconfirm the accessibility of both lactam tautomers in thesolid state and their assembly into complex intermolec-ular H-bonded networks; addition of a substituent doesnot preclude similar tautomerism and H bonding.

An ORTEP drawing of 2-diethylamino-6-methyl-5-n-propyl-4(3H)-pyrimidinone with the crystallographicnumbering system is shown in Fig. 3. Selected bonddistances and angles are reported in Table I, impor-tant intermolecular contacts in Table II, and a packingdiagram of 2-diethylamino-6-methyl-5-n-propyl-4(3H)-pyrimidinone is presented in Fig. 4. The asymmet-ric unit of 2-diethylarnino-6-methyl-5-tt-propyl-4(3H)-pyrimidinone contains two crystallographically distinct

Fig. 3. ORTEP drawing of 2-diethylamino-6-methyl-5-n-propyl-4(3H)-pyrimidinone with 30% probability thermal ellipsoids.

molecules in the monoclinic space group P21/n that areH-bonded about a center of inversion to form planar-dimers. The location of the hydrogen atoms on N(l)along with the lengths of the C—N and C=O bonds(Table I) unambiguously prove that 2-diethylamino-6-methyl-5-n-propyl-4(3H)-pyrimidinone exists as theN3 tautomer in the solid state. The pseudo-symmet-ric dimers are parallel to each other and packed inchains where heavy atoms of the same kind are super-imposed and brought in close proximity; the existenceof these packs can be ascribed to possible T-interac-tions; however, none of the distances between dissimilardimers are shorter than the expected van der Waals con-tact. The strong N(1)—H. . .O intermolecular hydrogenbonds from the N(1)—H group of one molecule to theC=O group of the adjacent molecule within the dimerare 2.804 A long and approximately linear (1)—H. . .Oangle is 174.7°; see Table II). In addition, the shift ofthe C=O stretching frequency to lower wave num-bers in the IR spectrum of 2-diethylamino-6-methyl-5-«-propyl-4(3H)-pyrimidinone (see the Experimental sec-tion) is consistent with an N3-type tautomeric form thatis strongly hydrogen bonded in the crystal.

Hydrogen bonding is a major organizing force inmany organic crystals. There have been numerous attemptsto rationalize the hydrogen-bonded arrangements, andultimately several empirical rules have been devised forpredicting preferred patterns [19]. In general, hydrogen-bonded crystal structures are the result of a compro-mise between two conflicting factors—the strength andthe number of hydrogen bonds within a crystal pack-ing scheme—and this is why they are so difficult to pre-dict. In addition, other nonbonded interactions or the crys-tallization solvent may influence significantly the pack-ing arrangement. Bertolasi et al. analyzed a large num-


Table I. Selected Experimental and Calculated Geometric Parameters (Bond Distances in A; bond Angles in Degrees)for 2-Diethylamino-6-methyl-5-n-propyl-4(3H)-pyrimidinone

Atom

N(1)-C(4)N(1) — C(l)N(1)— H(1)N(2)— C(4)N(2) — C(3)N(3)— C(4)N(3)— C(7)N(3) — C(5)C(1)— OC(1) — C(2)C(2)— C(3)C(2) — C(10)C(3) — C(9)N(1) — C(1)— C(2)C(1)— C(1)— C(3)C(2)— C(1) — N(2)C(4)-N(1)— C(5)C(4)— N(1)— C(7)N(1)— C(1) — C(2) — C(3)C(3)— N(2) — C(4) — N(1)C(10) — C(2)— C(3) — C(9)O— C(1)— N(1)— H(1)N(3)— C(4) — N(1) — H(1)

Exp.

1.363(2)1.387(2)0.980(2)1.325(2)1.378(2)1.359(2)1.461(3)1.465(3)1.243(2)1.431(3)1.362(3)1.503(3)1.500(3)

115.99(17)118.15(17)124.18(18)123.54(16)119.75(17)

0.25(17)1.00(17)3.35(17)1.26(17)1.70(16)

HF/6-311G**

1.3561.3930.9931.2891.3701.3521.4561.4621.1991.4491.3551.5121.505

114.53117.24124.64123.38119.20

1.030.630.301.801.39

B3LYP/6-31G*

1.3701.4151.0121.3141.3741.3681.4681.4611.2291.4491.3791.5111.509

114.14118.08124.34122.92119.05

1.130.540.372.041.99

ber of crystal structures that form neutral intermolecu-lar hydrogen bonds and concluded that the shortest (orstrongest) intermolecular hydrogen bonds between neu-tral molecules are controlled by a synergism of hydrogen-bond strengthening and T-delocalization enhancementdubbed RAHB (resonance-assisted hydrogen bonding)[19c, d].

Neutral N—H . . .O hydrogen bonds display a largespectrum of N. . .O distances, typically from 2.7 to 3.3A, and by comparison, the N—H . . .O distance of 2.804A in 2-diethylamino-6-methyl-5-n-propyl-4(3/f )-pyrim-idinone is rather short, implying a strong hydrogen bondproduced by a resonance-assisted structure. The2-diethylamino substituent adds an extra conjugationpathway, enhancing the T-polarizability and shorteningthe hydrogen bond. The tautomer occurrence is indu-bitably affected by the formation of such strong hydrogenbonds; however, other nonbonded interactions in the crys-

tal and packing effects should not be neglected. On thisaccount, the tautomeric preference of 2-diethylamino-6-methyl-5-n-propyl-4(3H)-pyrimidinone for the N3 formin the crystal can be viewed as an optimum arrange-ment that allows for the hydrocarbon chains to be closelypacked and benefits from very strong RAHB between theamidic functionalities, whereas in the case of N1 tau-tomers the compromise between a tight packing of theexocyclic substituents and strong hydrogen bonds cannotbe attained. The tautomer occurrence of 2-diethylamino-6-methyl-5-n-propyl-4(3H)-pyrimidinone in the solid stateappears to be a trade-off between crystal packing andhydrogen bonding.

The bond lengths and angles in 2-diethylamino-6-methyl-5-n-propyl-4(3H)-pyrimidinone appear consis-tent with the general pattern of 2-amino-5-pyrimidinonesfound in previously determined crystal structures [8c,14c, 15, 16]. In numerous pyrimidine structures the inte-rior bond angle is usually smaller at the ring nitrogenbearing a lone pair of electrons than at the protonatednitrogen, owing to valence-shell electron pair repulsion;in our case LC(3)—N(2)—C(4) (117.04°) is less thanLC(1)—N(1)—C(4) (122.29°) in good agreement withconventional cases. Furthermore, the bonds about N(1)are weaker and longer than those to N(2). The rather long

Table II. Intermolecular Hydrogen Contact Distances (A)and Angles (Degrees) of 2-Diethylamino-6-methyl-5-n-propyl-

4(3H)-pyrimidinone

D — H. . .A

N(1)— H(1). . .O

d(D — H)

0.98(2)

d(H. . .A)

1.83(2)

d(D. . .A)

2.804(2)

L(DHA)

174.7(2)


The sum of all bond angles is 359.9° for both N(1)and N(3), and thus their configuration is essentially pla-nar. The methyl group is not placed on the exteriorbisector of the C(2)—C(3)—N(2) angle; instead it isbent toward N(2) so that LC(2)—C(3)—C(9) exceedsLN(2)—C(3)—C(9) by about 8°. Similarly, the propylgroup bends away from the methyl group toward thecarbonyl because of increased double bond characterof the C(2)—C(3) bond (L.C(3)—C(2)—C(10) exceedsLC(1)—C(2)—C(10) by about 8°); the twist between theC(10)—C(2) and C(3)—C(9) bonds is 3.35°. The largestdeviation of a ring atom from the least-squares planethrough the six ring atoms is 0.009 A for N(1) (C(4) devi-ates by 0.007 A), and the largest deviation of a substituentis 0.057 A for C(10), (C(9o) deviates by 0.031 A, N(3) by0.028 A, and O by 0.009 A, respectively).

Fig. 4. Packing of 2-diethylamino-6-methyl-5-n-propyl-4(3H)-pyrim-idinone molecules: (a) the H-bond arrangement in dimers; (b) detailedview of the packing pattern.

C=O bond distance of 1.243 A and the C(4)—N(3)bond distance of 1.359 A, intermediate between a singleand double bond, are expected for this class of compoundsand suggest considerable conjugation and delocalizationof the exocyclic N(3) lone pair of electrons within the ring;the corresponding bond distances in isocytosine are 1.246A and 1.324 A, respectively. The 4-pyrimidinone ring andits substituents remain almost coplanar.

Ab Initio and DFT Studies

All quantum-chemical calculations were carried outusing the SPARTAN program (version 5.0, Wavefunc-tion Inc., Irvine, CA), running on an SGI Indigo2 work-station, and include full geometry optimization. The cal-culations do not take account of the interactions withthe environment and thus are more suitable to be com-pared with molecules isolated in an inert (gas-phase) orless perturbing environment (matrix). More recently, tau-tomeric equilibria have been studied with the use of thematrix isolation technique combined with IR absorptionspectroscopy, which is equivalent to gas-phase investiga-tions. Low-temperature matrix IR spectroscopy revealedthe clear predominance of the amino-hydroxy form ofisocytosine (AH) in argon matrix; the keto-enol equilib-rium constant for isocytosine was determined to be 0.15[20]. Similarly, matrix studies of 6-methylisocytosine[21], guanine [22], and 4-pyrimidinone [23] revealed theenol tautomeric forms (AH) for the first time.

Knowledge of the energetics of tautomerism canprovide useful information on the intrinsic stability oftautomers. The ab initio and DFT computational resultsfor the N1, N3, and AH tautomers of 2-diethylamino-6-methyl-5-n-propyl-4(3H)-pyrimidinone are summarizedin Table III. Due to disk space limitations and lim-ited computer time allotment, the calculations werenot possible at the MP2 level. To account for elec-tron correlation in the optimization of monomeric tau-tomers, we used the hybrid density functional of Becke'snonlocal three-parameter exchange functional with theLee-Yang-Parr correlation functional (B3LYP) [24].Among the two lactam forms of 2-diethylamino-6-


Table III. Relative Energies (AE; in kcal/mol) of the Tautomers of2-Diethylamino-6-methyl-5-n-propyl-4(3H)-pyrimidinone Calculated

by Various Computational Methodsa

2-Diethylamino-6-methyl-5-propyl-4(3H)-pyrimidinone

Method/AE

HF/3-21O*AEHF/6-31G*AEHF/3-21G*A£HF/6-31G*AEB3LYP/6-31G*AE

Nl (H— N1)

-700.95870+ 10.25

-704.87549+ 10.10

-704.91091+ 10.00

-705.04502+9.97

-709.42871+9.78

N3 (H — H3)

-700.975030.0

-704.891580.0

-704.926840.0

-705.060910.0

-709.44428-0.04

OH

-700.97211+ 1.83

-704.89205-0.29

-704.92995-1.95

-705.06321-1.44

-709.444210.00

aAll structures were fully optimized.

methyl-5-n-propyl-4(3H)-pyrimidinone, N1 and N3, theN3 tautomer is calculated to be significantly more sta-ble by all computational methods. Both HF/6-311G**

and B3LYP/6-31G* methods calculate small energy dif-ferences between the most stable amino-oxo form, N3,and the amino-hydroxy tautomer AH (Table III). Thus,we anticipate the coexistence of the AH and N3 tau-tomers in the gas phase or in matrices, in good agreementwith experimental data reported for similar compounds[20-23]. The HF relative energies of the three tautomersconverge with the use of systematically improved basissets and point to the necessity of inclusion of d-typefunctions in the basis set for more accurate predic-tions.

There is excellent correspondence between theexperimental and the HF/6-311G** or B3LYP/6-31G*

calculated structures of the N3 form (see Table I) eventhough it is expected that the strong intermolecular Hbonds will affect significantly the molecular geome-try in the crystal. Most differences between ab initiocalculations and experimental data on the bond dis-tances for nonhydrogen atoms are within 0.013 A onthe average (0.003 A to 0.044 A). The mean differ-ence in bond angles between nonhydrogen atoms isapproximately 1.04°. The largest differences in bondlengths are: C(1)—O 0.044 A, N(2)—C(4) 0.036 A,and C(1)—C(2) 0.018 A; the most significant deviationsin bond angles in the crystal versus the HF/6-311G**

structure are displayed by LN(2)—C(3)—C(9) 2.362°,LO—C(1)—C(2) 2.152°, LC(2)—C(3)—C(9) 1.893°,LN2—C4—N3 1.651°, andLN1—C1—C2 1.462°. Asexpected, the net effect of intermolecular H bonding is

the elongation of the C=O donor group in the crys-tal, 1.243 A versus 1.199 A in the calculated ab ini-tio structure, whereas the N(1)—H bond length remainsbasically unchanged (see Table I). The DFT optimizedgeometry displays in general longer bond lengths thanthe experimental or the ab initio values. The DFT meandifference in bond distances for nonhydrogen atoms issimilar to the ab initio deviation of 0.013 A; however,the largest differences in bond lengths are: N(1)—H(1)0.032 A, N(1)—C(1) 0.028 A, and C(2)—C(3) 0.017A (Table I).

EXPERIMENTAL

Synthesis of 2-Diethylamino-6-methyl-5-n-propyl-4(3H)pyrimidinone

2-Diethylamino-6-methyl-5-n-propyl-4(3H)-pyrimi-dinone was synthesized by condensation of the Na eno-late of ethyl 2-propyl-acetoacetate with N,N-diethyl-guanidinium nitrate, following previously reportedmethodologies [14d]. Single crystals suitable for X-rayanalysis were grown by slow evaporation of a saturatedsolution of 2-diethylamino-6-methyl-5-n-propyl-4(3H)-pyrimidinone in acetone. 1H NMR (CDC13) d 11.35 (s,1H), 3.53 (q, 4H), 2.34 (t, 2H), 2.16 (s, 3H), 1.44 (m,2H), 1.16 (t, 6H), 0.91 (t, 3H); 13C NMR (CDC13) d165.9, 162.8, 150.6, 110.5, 41.7, 27.3, 22.2, 22.1, 14.2,13.2; mp 121°C; IR (KBr) vmax 1649 cm-1; MS (El) m/zfor C12H21N3O 223 (M+, 20), 208 (19), 195 (11), 194(100), 180 (15), 151 (8), 96 (13).

Crystal Data

X-ray crystallographic measurements were carriedout on a Siemens SMART CCD diffractometer withgraphite-monochromated Mo Ka radiation (X = 0.71073A) operated at 50 kV and 40 mA. The structure wassolved by direct methods and refined by full-matrix least-squares techniques on F2 using the SHELXTL softwarepackage [25]. The intensity measurements were carriedout by the w - 20 scan technique; absorption correctionswere applied using SADABS, part of the SHELXTLsoftware package. All nonhydrogen atoms were refinedanisotropically. Hydrogen atoms were located from dif-ference maps and refined isotropically. The two mostprominent peaks in the final difference Fourier map were+0.284 and -0.220 e/A3. A summary of the crystal-lographic data including cell information, data collec-


Table V. Atomic Coordinates (x104) and Equivalent IsotropicDisplacement Parameters (A2 x 103) of 2-Diethylamino-

6-methyl-5-n-propyl-4(3H)-pyrimidinone

Atom

N(1)N(2)N(3)C(1)C(2)C(3)C(4)C(5)C(6)C(7)C(8)C(9)C(10)C(11)C(12)0H(1)H(5A)H(5B)H(6A)H(6B)H(7A)H(7B)H(8A)H(8B)H(8C)H(9A)H(9B)H(9C)H(10A)H(10B)H(11A)H(11B)H(11C)H(12A)H(12B)H(12C)

X

6342(2)8046(1)7220(2)6291(2)7190(2)8015(2)7211(2)6397(2)5277(2)8130(2)9295(2)8975(2)7177(2)7914(3)7787(3)5487(1)5720(2)6888(2)6164(2)4800(2)5560(2)4700(2)8280(2)7722(2)9690(2)9820(2)9110(2)9550(2)9383(2)8590(2)7480(2)6340(2)7600(2)8770(2)8270(2)6930(3)8070(2)

y

1654(3)4106(3)

910(3)2888(4)4883(4)5400(4)2254(4)

-1302(4)-414(6)1552(5)

10(5)7492(4)6193(4)4720(5)5900(6)2222(3)

280(5)-2550(4)-2140(4)

750(5)430(4)

-2080(6)3490(5)1190(4)550(5)320(4)

-2030(6)7360(5)7290(4)9230(6)7970(5)6340(4)2790(5)4630(5)5020(5)5730(5)7760(6)

z

426(1)742(1)

1349(1)-118(1)-223(1)

210(1)832(1)

1481(1)1805(1)1795(1)1725(1)

142(1)-815(1)

-1272(1)-1878(1)

-473(1)467(8)

1738(8)1117(8)1560(1)2199(9)1920(1)1779(8)2208(9)1339(1)2067(1)1714(1)453(1)

-251(9)98(1)

-781(8)-961(8)

-1277(9)-1152(9)-2177(1)-2028(1)-1874(1)

U(eq)

26(1)28(1)31(1)26(1)26(1)27(1)25(1)31(1)50(1)37(1)48(1)34(1)32(1)41(1)52(1)34(1)51(7)38(6)23(5)61(8)47(6)84(9)44(6)40(6)65(8)51(6)75(8)64(8)40(6)69(8)48(6)43(6)51(6)58(7)60(7)61(8)64(8)

CONCLUSION

The crystal structure of 2-diethylamino-6-methyl-5-rt-propyl-4(3H)-pyrimidinone has been reported. Onlythe lactam tautomer protonated at N3 is present in thecrystal, in good agreement with the quantum-chemi-cal results. Ab initio and DPT calculations estimate adifference of ca. 10 kcal/mol between the two lactamtautomers, Nl and N3; however, the calculated energydifference between the most stable tautomer, N3, andthe enol form, AH, is small at both HF/6-311G** and

B3LYP/6-31G* levels of theory, leading to the theoreti-cal prediction that the two tautomeric forms coexist inthe gas phase or in matrices.

SUPPLEMENTARY MATERIAL AVAILABLE

The anisotropic displacement parameters and hydro-gen coordinates in the crystal, as well as the Carte-sian coordinates of the atomic centers at the theoreti-cally predicted equilibrium geometries of the tautomersof 2-diethylamino-6-methyl-5-n-propyl-4(3H)-pyrimidi-none, are available from the authors of this work uponrequest.

tion, and refinement parameters is presented in TableIV. The final atomic coordinates and isotropic displace-ment factors are listed in Table V. Crystallographic datahave been deposited at the Cambridge CrystallographicData Centre (CCDC) and allocated the deposition num-ber CCDC 112121.

Table IV. Crystallographic Data and Refinement Parameters for2-Diethylamino-6-methyl-5-n-propyl-4(3H)-pyrimidinone

2-Diethylamino-6-methyl-5-n-propyl-4(3H)-pyrimidinone

FormulaFormula weightCrystal systemSpace groupZUnit cell dimensions

abca = y0

VolumeCrystal sizeDensity (calculated)Absorption coefficient uF(000)6 range for data collectionIndex ranges

No. reflection collectedNo. unique reflections

(Rint = 0.0676)No. reflections used in refinementNo. parametersNo. restraintsR indices (l >2a(I))R indices (all data)Goodness of fit on F 2

Extinction coefficient

C12H21N3O223.32MonoclinicP21/n (#14)4

11.0460(8) A5.0064(4) A22.8358(17) A90°90.521(2)°1262.78(17) A3

0.47 x 0.18 x 0.13 mm1.175 g/cm3

0.077 mm-1

4881.78< 0 < 25.00-13 < h < 8; -5 < k < 5;

-27 < l < 275978

219821982300R1 = 0.0502, wR2 = 0.1116R1 = 0.0808, wR2 = 0.12170.9480.013(2)


ACKNOWLEDGMENTS

The authors would like to acknowledge ProfessorJames E. Jackson (MSU) for providing X-ray diffractionfacilities.

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25. SHELXTL: Structure Analysis Program 5.1; Bruker AXS, Inc.,Madison, WI, 1997.

molecular structure of an isocytosine analog: combined x-ray structural and computational study of...

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