Indian Journal of Chemistry Vol. 39B, November 2000, pp. 826·835

Influence of competing A 1,3 -strain on the conformational preferences of Nb N4-diformylpiperazines

R Jeyaraman' & R Murugadoss Department of Chemistry, Bharathidasan University, Tiruchirappalli 620024, India

Received 6 May 1998; accepted (revised) 14 March 2000

The conformational preferences of NJ,N4-diformylpiperazines 9-12 have been studied using NMR spectral techniques and semi empirical molecular orbital calculations. Each of the diformylpiperazines 9·11 have been found to exist as an equilibrium mixture of four rotamers resulting from the restricted N-C rotation at the two N-C=O bonds. All the four rotamers (anti-anti, anti-syn, syn-anti, syn-syn) of 9 are found to adopt the twist-boat (B4) conformations. Similarly all the four rotamers of 11 prefer flipped chair (CA) conformations. On the other hand the diformylpiperazine 10 has been found to adopt different ring conforinations depending upon the N-CHO rotameric states (B4 for the rotamer A, B3 in the cases of rotamers B and D, and CA for the rotamer C). The AU-strain and the resonance energy (arising from the delocalisation of the lone pair of electrons on the nitrogen) have been found to be the most important factors in determining the conformational preferences of all the piperazines investigated. The semiempirical molecular orbital calculations supported the conformational preferences and the nature of the conformational equilibria derived from the NMR results.

The conformational preferences and stereodynamics of several N-X=Y (N-NO, N-GIO, N�R, N-COOR) substituted cis-2,6-diarylpiperidines, cis-2, 7 -diphenyl­hexahydrodiazepines and cis-2.4-diaryl-3-azabicyclo­[3.3.1]nonanes have been studied using NMR and X-ray analysisl-5. The conformational equilibrium observed in these compounds was attributed to the existence of two rotamers (syn and anti) arising from the restricted rotation around the N-NIN-C single bond) at ambient temperature in the cases of N-nitroso and N-formyl derivatives and at lower temperatures in the cases of other N-acyl derivatives. The introduction of these electron withdrawing groups was found to alter the conformational preferences of these compounds from the chair to twist-boat or twist-chair forms.

The N-C=O group in these molecules can be either coplanar or perpendicular with reference to the C2-NI-C6 plane6• When the -N-C=O group is coplanar the lone pair of electrons on the nitrogen is in conjugation with the -C=O function. The conjugation creates a partial double bond character at N-C bond and leads to a restricted rotation around this bond which in tum results in a magnetic nonequivalence of the ring carbons and the attached protons.

The substituents at the equatorial positions alpha to the nitrogen exhibit a severe nonbonded interaction with the coplanar N-C=O function which is termed as

Pseudo Allylic strain or A 1,3 -strain 7• With a view to

understanding the competition between the A 1.3 -strain at more than one site by introducing two N-C(H)=O groups in diazacycles the stereochemical equilibria in

various a,a' -substituted piperazines were investigated by using NMR and semiempirical molecular orbital calculations. The relativ.e influences of the A I.3 -strain, 1,3-diaxial interactions, resonance energy (due to the delocalisation of lone pair of electrons in nitrogen along N-C=O group), on the conformational preferences of piperazine ring have been studied.

Results and Discussion . The condensation of benzil with 1,2-dialkyVarylamines afforded the 2,3-diphenyl-5,6-alkyVaryldihydropyrazines8

1- 4. The piperazines 5-8 have been synthesized by the reduction of the dihydropyrazines 1- 4 using sodium borohydride in ethanol9 (Scheme I). The structures of the piperazines 5-8 were confIrmed with the help of IR, mass, IH NMR and J3C NMR spectral data. The molecular ion peaks and the fragmentation pattern agreed, with the structures of the piperazines 5-8. The signals due to the amine NHs of the piperazin�s 5-8, appeared at B 1.87, 1.85, 1.96, 1.78, respectively. They were confIrmed by the disappearance of the signal in the D20 exchanged IH NMR spectra of the corresponding piperazines.

Relative configurations of the substituents and the ring conformation of the piperazines 5-8. The

lEY ARAMAN et al.: CONFORMATIONAL PREFERENCES OF N I' N. -- DIFORMYLPlPERAZINES 827

H R1X):Al H-CO-O-COCH; R2 N Al I H

5-8

1,5,9 2,6,10 3,7,11 4,8,12

Schemel

Ph Ph H H

observed coupling constants of 10.88, 8.7, 9.38 Hz, respectively, for the H5 and H6 protons of the piperazines 5-7 suggest that these two protons are antiperiplanar to each other. Hence the substituents (phenyUalkyl) at the C5 and C6 positions are probably trans to each other.

In the case of 5-isopropyl-2,3,6-triphenylpiperazine 5, the vicinal coupling constant observed for the H2 and H3 protons is 8.78 Hz suggesting anti peri planar arrangement between these two protons and hence the relative orientation of the two phenyl groups at C2 and C3 positions is likely trans to each other. In order to confmn the orientations of the substituents 2D-NOESY spectra were recorded for the piperazine 5. The observation of NOEs between the H2 and H6, H3 and H5 protons clearly indicated that all these four protons occupied the axial positions and hence the alkyl and the phenyl substituents were orientated equatorially. The large vicinal coupling constants and the observed NOEs of 5 can be well explained by assuming a chair conformation with all the phenyl and isopropyl groups occupying equatorial orientations.

The benzylic protons (H2 and H3) of 5-methyl-2,3,6-triphenylpiperazine 6 were observed as a singlet and therefore further NOE studies were made for the assignment of the relative orientation of the phenyl groups in the C2 and C3 positions. The NOE difference spectra· were recorded by irradiating individually the multiplet corresponding to H5 and the doublet corresponding to H6 protons. In both the irradiations the NOE enhancements of 11.3% and 8.6%, respectively, were observed at the signal

corresponding to the benzylic protons (singltt). This observation could be explained only when the piperazine adopt a chair conformation in which all the four ring protons attached to the carbon atoms oriented axially. The other boat forms and the flipped chair form failed to explain at least one of the NOE enhancements. Hence on the basis of the observed NOEs and the vicinal coupling constant it was concluded that the piperazine 6 prefers to adopt a chair conformation with all the three phenyl groups and the methyl group occupying equatorial orientations. The semiempirical molecular orbital calculations also indicated a preference for the chair form over the other boat forms by more than 3 kcaUmol.

NhN4-Difonnylpiperazines 9-12. The reaction of acetic-formic anhydride with piperazines 5-8 in dry benzene and triethylamine at reflux temperature yielded the diformyl derivatives 9-12 (Scheme I). The structures of the N\oN4-diformylpiperazines 9-12 were confirmed with the help of mass, IR, lH and l3C NMR spectral data and elemental analysis. In the IR spectra of the NIoN4-diformylpiperazines 9-12 both the NH stretching bands of the parent piperazines 5-8 were absent and a new C=O stretching band at around 1670 cm-1 was observed. In the mass spectra, the molecular ion peaks were observed at mJz 412, 384, 308 and 294 for 9, 10, 1 1 and 12, respectively, and the fragmentation {'attern of each compound agreed with its structure.

The signals due to the NH protons, which appeared at B 1.87, 1.85, 1.96, 1.78 ppm in the lH NMR spectra of the parent piperazines 5-8

· disappeared in the

formyl derivatives 9-12 (Scheme I). All the foregoing evidence confirmed that the compounds 9-12 are the diformyl derivatives. The lH and l3C NMR spectra of the NIoN4-difonnylpiperazines 9-12 were found to be complex' due to the observation of four signals corresponding to each one of the magnetiC nuclei. The assignments of the lH and l3C NMR signals of the piperazines 9-12 were made with the help of 20 NMR techniques such as COSY, lH_l3C HETCOR and NOESY (Tables I and II).

IH and l3C NMR spectra and the nature of conformational equilibria in 9-12. In the lH and l3C NMR spectra of the diformylpiperazines 9-11, four sets of signals with different intensities were observed corresponding to each one of the magnetic nuclei. The four sets of signals have been shown to be due to the existence of four conformers in an equilibrium and not due to admixture of configurational isomers on

828 INDIAN J CHEM. SEC B. NOVEMBER 2000

Table I_JH NMR spectral data (in S. ppm)of NJ,N4-difonnylpiperazines 9-11

Compd H2 H3

9 Rotamer A** 4.95 (d, 1 1 .23) 4.35 (d, 1 1 .23) B 5.21 (d, 1 0.30) 4.42 (d, 1 0.25) C 5 .29 (d, 9.28) 5 . 1 3 (d, 9.28) D 4.93-5.00 (merged) 4.93-5.00 (merged)

10 Rotamer A 4.45 (d, 11.23) 4.99 (d, 1 1 .24) B 5 .88 (d, 4.39) 4.85 (d, 4.88) C 5 . 1 3 (d, 6.34) 5 .70 (d, 6.84) D 6.43 (s)

1 1 Rotamer A 5 .03 (d, 2 . 1 0) 5 . 56 (d, 2.30)

B 5.60 (s) 6.39 (s)

C 6.30 (s) 5 . 19 (5) D 6.49 (s) 6.55 (s)

*Multiplicities and 'f values (in Hz) are given in parentheses.

H5

4.93-5.00 (merged) 4.93-5.00 (merged) 3.7 1 (d, 1 0.74) 3 .83 (d, 1 1 .23) 5.44 (m) 4.82 (m) 4.30 (m) 4.09 (m) 4.48 (m)

3.82-3.90 (merged)

4.63 (m)

3.82-3.90 (merged)

H6

6. 1 1 (s) 5 .17 (s) 5 .96 (s) 6.45 (s) 5 . 8 1 (s) 4.43 (d, 8.78) 5 .25 (d, 4.5) 4.35 (d, 8 .78) 3.78 (dd, 1 4.6, 6.0) 3.48 (dd, 14. 1 ,7.9) 3 .82-3.90 (merged) 3.09-3.38 (merged) 3 .59 (dd, 1 3 .5 , 4.9) 3 .09-3.38 (merged) 3.40 (dd, 1 3 .3, 4.3) 3 .09-3.38 (merged)

1 .67 (d, 6.83) 1 . 1 7 (d, 6.35) 1 .60 (d, 6.83) 1 .09 (d, 6.35) 1 . 16 (d, 6.50)

1 .00 (d, 6.90)

0.92 (d, 6.80)

0.85 (d, 7. 10)

"Rotamers A, B, C and D represent the rotamers anti-anti, syn-anti, anti-syn, syn-syn, respectively, where syn and anti refer to the 'orientation of the C=O group with reference to the C2 carbon.

9

10

11

Table II - J3C NMR spectral data (in 8, ppm) of Nl>N4-diformylpiperazines 9-1 1

C2 C3 C5 C6

Rotamer A* 65.0 62.9 56. 1 5 1 .4 B 56.0 6 1 .6 55 .7 6 1 . 1 C 6 1 .3 59.4 64.8 53 .0 D 5 1 .0 52.4 65.4

Rotamer A 62.5 65.0 45.9 54.6 B 58. 1 6 1 .1 5 1 .2 60.7 C 59.5 52.8 D 53.0 52.7 62.2

Rotamer A 60.7 58.7 46.4 40.5 B 5 1 .7 58.5 45. 1 45.4 C 56.6 50.4 49.4 40.7 D 49.0 49.5 49.8 46.0

1 8 .4 20.9 2 1 .9 1 9.8 1 8.8 1 8 . 1 2 1 . 1 20.3

the basis of constant physical data after repeated recrystallizati ons.

The four confonners may be either different ring conformations such as chair, flipped chair, boat, twist-boat (Figure 1) in which the orientation of the fonnyl groups is the same or four N-C=O rotamers arising from the restricted rotation around the N-C single bond (syn-syn, syn-anti, anti-syn, anti-anti; the syn and anti refer to the orientation of fonnyl oxygen with reference to the C2 carbon (Figure 2).

The shielding and deshielding of a,a' -carbons with respect to those in the parent piperazine depend on the orientation of the fonnyl group. If the C=O group is syn to the C2 carbon, the C2 carbon is shielded because of the eclipsing interaction between N-C2 and C=O bondslO. The chemical shift values of the C2 carbon of 9 are 8 65.0, 61.3,56.0 and 51.0 ppm, while

H 0::::( ° Fh

NrtH Rl�N R2 Fh

Figure 1

. that of the corresponding signal of the parent piperazine is 8 68.8 ppm. This observation suggests that the orientation of c=o group is syn in the case of the C2 carbon signals which absorbs at higher field (8 56.0 and 51.0) and is anti for the C2 carbon signals

,which absorb at lower field (8 65.0 and 61.3). Similar

JEYARAMAN et al.: CONFORMATIONAL PREFERENCES OF NI, N4 � DIFORMYLPIPERAZINES 829

0yH

R 4�Rt

R:�N1 2

Rt OJ--H Rotamer A (anti-anti) H'10

R1:cNXRt

R2 N Rt oJ--H

Rotamer C (anti-syn)

O� H

R1:cNXRt

R2 N Rt H�O

Rotamer B (syn-anti) H'f 0

R1:cNXRt

R2 N Rt H�O

Rotamer 0 (syn-syn)

Rgure 2

observation, which was found for other ring carbons (C3, C4 and C6; Table II) also, suggests that the conformational equilibria observed is likely due to the existence of the four rotational isomers arising from syn and anti orientations of the formyl groups at NI and N4 ends. This anisotropic behaviour of the formyl groups was observed for all the four piperazines 9-12 studied.

The observed vicinal coupling constants of about 10 and 0 Hz, respectively, between the H2 and H3 protons e JH2,H3) and the H5 and H6 protons e JH5,H6) for all the four sets of signals (Table I) of the diformylpiperazine 9 indicate that all the conformers involved in the equilibria adopt the same ring conformation. Similarly the vicinal coupling constants of 0 e JH2.H3) and 5-7 Hz e JH5,H6) for all the four sets of signals of H2, H3, H5 and H6 protons for 11 are also same indicating the same ring conformation for all the four conformers. Hence the conformational equilibria observed is attributed to the existence of the four rotational isomers (Figure 2).

Orientation of the fonnyl functions. Broadening of proton signals was observed in the IH NMR spectra at 50°C. The well-resolved signals (four signals corresponding to each one of the protons) at ambient temperature and the broadening at higher temperature indicated that the N-C=O groups may adopt a coplanar orientation with respect to the C2-NI-C6 and C3-N4-C5 planes of the molecule with N-C=O conjugation. The coplanar orientation of the C=O groups in the compounds 9-12 has been further confirmed from the following observations: (i) the greater de shielding (�o =1.5-2.5 ppm) of H2, H3, H6

and H5 protons compared to the parent piperazines II , (ii) the greater shielding (about 10 ppm) of C2, C3, C5 and C6 carbons.

Nl,N4-Difonnyl-t-5-isopropyl-r-2/-3,c-6-triphenyl­piperazine 9. Assignment of 13C NMR signals. The assignments of l3C signals of 9 were made with the help of l3C_IH HETCOR spectrum as well as by comparing the chemical shifts with those of the parent piperazine 5 (Table II). In general the a-carbons in N-formylamines appear upfield if the C=O group is syn to them than when it is anti 10. The C2 carbon of 9 gives four signals (0 65.0, 56.0, 61.3 and 51.0) due to the anisotropic effect of the formyl groups. These four signals can be grouped into two pairs on the basis of their proximity to each other. The pair of signals observed at relatively lower field (0 65.0 and 61.3) corresponded to the conformers A and C (Figure 2). The second set of signals were observed at higher field (0 56.0 and 51.0) which corresponded to the conformers B and D (Figure 2). The downfield appearance of the C2 signals of A and C pair with respect to those of the B and D pair indicated that in the former set of rotamers the NI-formyl group is anti

to the C2 carbon, while in the latter it is syn (Table II). Among the four signals of the C5 carbon the

resonances due to the conformers C and D form a proximal pair (0 64.8 and 65.4 ppm, respectively) while those of A and B form another pair (0 56.1 and 55.7 ppm, respectively). Since the chemical shift difference of C5 signals within each pair of conformers is negligible (less than 1 ppm), the conformers in each pair are suggested to have the same orientation of the N4-formyl group. The l3C signals of the C5 in the C and D pair appear considerably downfield compared to those of the A and B pair, indicating that the N4-formyl is syn to C5 in the latter set of conformers, while it is anti in the former set. Similar analysis using l3C spectral data of C3 and C6 carbon signals have been carried out to assign the orientation of the a-formyl groups in all the four conformers.

The determination of syn and anti IH signals was made by employing the IH_l3C HETCOR spectrum, which gives cross signals for the syn and anti protons coupled with the respective syn and anti l3C signals for which the assignments were already made.

Ring confonnation. The large vicinal coupling constants of about 10-11 Hz (Table I) observed between H5 and CH< of the isopropyl group of the diformylpiperazine 9 indicate an antiperiplanar arrangement between these two protons and also the

830 INDIAN J CHEM, SEC B, NOVEMBER 2000

isopropyl group has static orientation (does not rotate freely).

The 'H NMR signals due to the benzylic protons at H2 and H3 appeared as two doublets at 8 4.95 and 4.35 ppm, respectively, corresponding to the rotamer A, at 8 5.21 and 4.42 ppm in the case of the rotamer B and at 8 5.29 and 5.13 ppm for rotamer C with coupling constants e J2H•3H) of 11.23, 11.23, 10.30, 10.25, 9.28 and 9.28 Hz, respectively. This pattern would be possible only if there is an equilibrium among the conformers or rotamers that do not involve any ring flipping such as chair-chair and chair-boat interconversions. Such a type of interconversion will convert the axial hydrogens into equatorial hydrogens and vice versa which result in major changes in the coupling constants within each pair.

The various possible ring conformations . likely adopted by the piperazines are collected in Figure 1 . The formylpiperazines 9-12 may adopt any one of the conformations (Figure 1) which can balance among various strain factors or any one of the intermediate twist form. In order to relieve the allylic strain the molecule may flip over to the alternate chair, twist-chair, twist-boat conformations with pseudo-axial phenyl groups retaining the coplanar N-C=O function with respect to C2-N-C6 plane.

The ring conformation was arrived at for the N1}/4-diformylpiperazines on the basis of the following factors: (i) The relative strain factors expected, while assuming a particular ring conformation among the various possible conformations, (ii) The observed vicinal coupling constant data (which in tum provided the dihedral angles expected by applying the Karplus relationship'2), (iii) The relative stability of the conformers predicted by the semiempirical molecular orbital calculations and the geometry of the optimized structures, (iv) The observed NOEs data.

The chair conformation (CE, Figure 1) with equatorial phenyl groups is highly destabilized by the A 1,3 -strain acting at both the N 1 and N4 ends. In this conformation all the four a protons H2, H3, H4 and H5 are at axial positions and the expected vicinal coupling constants e lzH.3H and 3

J5H.6H) are around 10-12 Hz, but the observed vicinal coupling constant of zero for 3

J5H,6H ruled out the possibility of this conformation. The semiempirical calculations also predicted relatively higher energy (about 10 kcalll11ol) for this conformation compared to the global minimum structure.

In the flipped chair conformation (CA) with axial

phenyl groups, the A ',J -strain is absent but the two phenyl groups and the phenyl-isopropyl groups would exhibit 1,3-diaxial interactions. Since all the a-hydrogens (H2, H3, H5 and H6) are at equatorial positions in this conformation the 3

lzH,3H and 3 J5H,6H

coupling constants are expected to be around 2-5 Hz. But the observed coupling constants of 11 Hz for 3lzH.3H and ° Hz for 3

J5H,6H (Table III), excluded the possibility of the chair conformation though this conformation was pointed out to be one of the most stable conformations in all of its four rotameric states by the calculations.

In the case of boat forms Bl and B2 one of the phenyl groups at 2 or 3 occupy axial position and the corresponding protons occupy equatorial position hence the expected vicinal coupling constant for H2

3 " 3 and H3 protons ( lzHe,3Ha or lzHa,3He) is around 2-5 Hz,

but the observed coupling constant is around 11 Hz,

Table III- Calculated relative heats of formation (kcal/mol) of difonnylpiperazines 9-12 by the AMI method

Compd Ring conforma­tion

9 CE CA Bl B2 B3 B4 BS B6

10 CE CA Bl B2 B3 B4 BS B6

11 CE CA Bl B2 B3 B4 BS B6

12 CE CA Bl B2 B3 B4 BS B6

anti-anti

1 7 .37

6.50

6.64 0.00 0.59

1 . 1 7 5. 19 7. 14

0.00 0.27 3 .82 3 . 39 0.58

1 .89 0.77 0.77

1 .58 0.00

0.97 1 .54 1 .54 0.97

AM I method Rotamers

syn-anti allli-syn syll-syn

1 6.22 1 8.60 1 .67 0.93 0.75 6.07 7.62 1 1 .37

7.27 3.45 4.53 2. 1 6 2.50 3.48 1 .72 5. 1 2

7.88 6.07

1 . 1 3 0.62 0.58 5.63 5.95 1 0. 1 0 5.47 5.75 1 .7 1 3.67 1 . 1 4 2.64 2.08 3.02 1 .52 4.9 1 1 .09 3.1 8 1 .18

6.70 0.05 0.38 0.26 4.02 6.39 8.52 6.47 2.04 0.00 2.63

2 .98 2.77

2 .75 2.99 7. 1 3 7. 1 3 0.21 0.21 0.82 2.44 6.42 6.46 2.44

1 .29 3.70 2.23

2.23 1 .63 3.70

lEY ARAMAN et al. : CONFORMATIONAL PREFERENCES OF N I' N. - DIFORMYLPIPERAZINES 831

excluding the possibility of these · two boat conformations. In addition, these boat forms would also be destabilized by the A 1.3 -strain at any one of the nitrogen ends (Nl or .N4) due to the interaction between the phenyl grOl�p (C2 or C6) and the N-CO or the phenyl at C3 or isopropyl group at CS and N-CO. Moreover these two boat forms were indicated to be higher energy forms than those of the other boat forms (B3-B6). Hence these two boat forms (Bl and B2) are excluded.

In the case of boat forms B3 and B6 also the expected vicinal coupling constant C J2H•3H) for the H2 and H3 protons is 2-S Hz, but the observed coupling constant is 11 Hz. Moreover the A

1.3 -strain is operating at any one of the nitrogen ends (Nl or N4) hence the possibility of N-formylpiperazine 9 assuming this conformation is also ruled out.

Thus the observed coupling constants (both the 3 hH.3H and 3 J5H.6H) can be well accommodated by assuming the boat conformations B4 or BS with a slight twist along the CS, C6 which makes the HS and H6 protons to assume a orientation in such a way that the protons are almost perpendicular to each other. The twisting along the CS and C6 was also observed in the AMI optimized structures of B4 and BS which is found to be one of the lower energy structures. The torsion angle (HS-CS-C6-H6) derived from the X -crystal structure of 1113 is 840 which also supported the NMR results of 0 Hz coupling constant between the HS and H6 protons.

Between the two boat forms (B4 and BS) the observed NOEs of the H2 with the methyl groups of the isopropyl group favour the boat form B4. In addition, the calculations also indicated that the boat form B4 is more stable than the boat form BS. All the foregoing evidence showed that the preferred conformation for the NhN .. - diformylpiperazine 9 is the boat form B4.

Hence it was concluded that the conformational equilibrium exihibited by 9 contains four rotamers anti-anti, anti-syn, syn-anti, syn-syn with population of 69%, 15%, 11 % and 5%, respectively, and all the four rotamers adopt twist boat conformations (B4, Figure 1).

N h N 4-Difonnyl-t-S-methyl-r-2, t-3, c-6-triphenyl­piperazine 10. In the case of the methyl substituted diformylpiperazine 10 the observed coupling constant data (Table 1) indicated that the rotamers may adopt different ring conformations for each one of the rotamers unlike the isopropyl substituted diformyl-

piperazine 9 in which all the four rotamers adopt the same ring conformation (B4). The coupling constant . 3 data observed for the rotamer A (JH2,H3 = 11.2 Hz, 3 JH506 = 0 Hz) showed that the rotamer A also adopts

B4 conformation similar to that of the rotamers of 9. On the other hand the rotamers B and D adopt another boat conformation B3 in which the rotamer D undergoes a slight twisting along the C2 and C3 bond. The observed coupling constants C JH2,H3 = 6.8 Hz, 3 JHS,6 = 4.5 Hz) indicated that the rotamer C may

adopt the boat form Bl .

N 1,N4-Difonnyl-t-S-methyl-r-2,t-3-diphenylpipera­zine 11. The observation of vicinal coupling constant of 0 Hz C hH.3H) between H2 and H3 protons in the case of rotamers B (syn-anti), C (anti-syn), and D (syn-syn) and of 2.2 Hz in the case of the rotamer A (anti-anti) for the diformylpiperazine 11 indicated that the rotamer A may adopt a slightly different ring conformation from the rest of the rotamers.

The vicinal coupling constant of 0 Hz C hH.3H) in the case of rotamers B, C and D and 2.2 Hz for H2 and H3 protons ruled out the possibility of the conformations CE, B4 and BS for 11 since the expected coupling constant between the H2 and H3 protons is 10-12 Hz for the conformations CE, B4 and BS. The boat form B l is destabilized by the AI•3-strain between either CH3 or Ph group and N-C=O group at the N4 end. In addition, both the Bl and B2 boat forms were indicated to be higher energy forms than those of the other boat forms (B3-B6). Hence these two boat forms (Bl and B2) are excluded.

The observed coupling constant of 0 Hz between the H2 and H3 protons can be explained by assuming' the conformations CA, B3 or B6 with a slight twisting alon' g the· C2 and C3 carbons. The slight twisting along the C2 and C3 carbons was found in both the �1�mi��ct��alro ��X� structure of 11. The dihedral angle between the H2 and H3 protons was found to be 8S.0° and 80.10, , respectively, from the �1 calculations and X-ray crystal studies. This geome�ry explained the zero coupling observed between H2 and H3 protons of the rotamers B, C and D for 11 in the CDCh solution. The coupling constant of 2.2 Hz between the H2 and H3 protons of the rotamer A indicates that the CA conformation of this rotamer does not undergo any twisting along the C2 and C3 bonds as experienced by the other conformers since both the -C=O groups adopt anti orientations and in turn there is no interaction between the bulky phenyl gIOupS and the I

832 INDIAN] CHEM, SEC B, NOVEMBER 2000

carbonyl groups. In addition the calculated AMI energies also indicated a strong preference for the conformation CA over the other boat forms. Hence it was concluded that the piperazine 10 exists most predominantly in a flipped chair form (CA). The X<rystal structure of 11 also showed the flipped chair conformation 13.

Nl,N4-Difonnyl-r-2,t-3-dipbenylpiperazine 12. The 'H and 13C NMR spectra showed only two sets of signals for the diformylpiperazine 12 indicating cbnformational equilibrium between only two rotamers. Among the two rotamers one which contributes more to equilibrium (major rotamer) was found to adopt unsymmetrical N-C=O orientations (rotamer B or C) and the other rotamer (minor rotamer) was found to adopt the same orientation either syn-syn (rotamer D) or anti-anti (rotamer A). The rotamers B and C (Figure 2) are same for the piperazine 12 because of the symmetry of the molecule. On the basis of the shielding and deshielding 13C chemical shift values (�8) of the C2/C3 and C5/C6 carbons with respect to the parent piperazine 8, rotamer B was assigned to the major rotamer and rotamer A was assigned to the minor one. The vicinal coupling constants e JH2.H3) of 3.3 and 0

. Hz between the H2 and H3 protons of the rotamer B and rotamer A, respectively, indicated that the rotamers may adopt the CA conformation among the possible ring conformations (Figure 2) with a slight twisting along the C2 and C3 in the latter case.

SemiempiricaI Molecular Orbital Calculations The heats of formation of various ring

conformations of the N"N4- diformylpiperazines 9-12 were calculated by semiempirical molecular orbital calculations using the AM 1 method available in MOPAC-614 in order to find the relative stability of the conformers.

For each N"N4-diformylpiperazines 9-12 all possible ring conformations, such as a chair (CE), a flipped chair in which the phenyl groups occupy axial positions (CA) and six boat forms B1-B6 (Figure 1) were considered. The optimization of these conformations was carried out by varying specific torsion angles (C2-NI-C=0, C3-N4-C=0, NI-C2-C3-N4, C2-C3-N4-C5 etc.), one at a time,

within the possible ranges in 10° increments.

Orientation of -N-C=O group A plot of AMI energies versus C2-NI -C=0,

f:3-N4-C=0 torsion angles indicated that the energy

minima occur at O±lO° and 180±1O° and energy

maxima at 90±20° and 270±20°. These results show a strong conformational preferences for the coplanar orientation of the -N-C=O groups with respect to the C2-NI-C6/C3-N4-C5 plane over the alternate perpendicular orientation. The calculated N-C bond lengths were found to be around 1.39 A, which are close to the averafe Sp2 N-C bond length (1.38 A) rather than the sp N-C bond length (1. 47 A). The shortening of N-C bond length showed the presence of a double bond character for N-C bond in the coplanar orientation.

Ring confonnations Table III shows the relative formation energies

obtained for various conformations (Figure 1) of the N"N4-diformylpiperazines 9-12 by the AMI method. The calculations indicated that the chair conformation (CA) is the most favourable form in most of the cases.

The results of the calculations also indicated an equilibrium among the four rotamers of the chair (CA) conformation. Though the boat form B4 in the case of 9 and B3 in the case of 11 was found to have lower energy than that of the CA form the energies of the other rotamers of the same boat form were found to be very high. Hence the observed equilibrium is likely the one corresponding to the rotamers with the CA conformation.

Conclusion

The stereochemical investigation on the diformylpiperazines 9-11 by NMR techniques showed the existence of a conformational equilibrium involving four rotational isomers ansing from the restricted rotation around the N-C single bond of the N-C=O groups. In the case of the difonnylpiperazine 12 only two rotamers A and B were found to be in equilibrium. All the four rotamers (anti-anti, anti-syn. syn-anti, syn-syn) were found to adopt the same ring conformation (twist-boat B4 for 9 and the flipped chair for 11). On the other hand the rotamers of the diformylpiperazinc 9 were found to adopt different ring conformations (B4 for the rotamer A, B3 in the case of rotamers Band D, and CA for the rotllmer C). The A'·3-strain and the resonance energy (arising from the delocalisation of the lone pair of electrons on the nitrogen) were found to be the most important factors in

. determining the conformational preferences of all the piperazines investigated. The semiempirical molecular orbital calculations supported the conformational preferences and the nature of the conformational equilibria derived from the NMR results.

JEYARAMAN et at.: CONFORMATIONAL PREFERENCES OF N1, N. - DIFORMYLPIPERAZINES 833

Experimental Section General. The melting points are uncorrected. The

IR spectra were measured on a Shimadzu IR-435 spectrometer in KBr pellets. The mass spectra were recorded on a Jeol J MS-D 300 spectrometer operating at 70 eV. The lH and l 3C N MR spectra were recorded on a Bruker WH-270 or Jeol GSX-400 instrument in CDCh solution. The two dimensional (COSY, NOESY, lH_l3C HETCOR) NMR spectra were recorded on a Bruker AMX-400 and Jeol GSX-400 NMR machine. The piperazinesl5 7 and 8 and the dihydropyrazines 1 and 2 were prepared using the literature proceduress.

Computational details. Owing to the large size of the piperazines 9-12, semiempirical quantum mechanical methods were employed for the computation of the formation energy of each conformer. The AMI method available in the MOPAC 6. 1 PC version was used to perform the calculations on Pentium personal computers. The optimization was performed by using an analytic gradient minimization method (BFGS, Precise option). Furthermore, eigenvector (EF option) procedure was used to lower the mean gradient up to values below 0.01 kcallmol.

t-5-Isopropyl-r-2,t-3,c-6-triphenylpiperazine 5. To a stirred solution of 5-isopropyl-2,3,6- triphenyl-5,6-dihydropyrazine (3 .52 g, 0. 1 mole) in ethanol (50 mL), sodium borohydride (0.72 g , 0.02 mole) was added in small quantities for about 1 hr. The mixture was heated under reflux for 30 min after the addition of sodium borohydride. The reaction mixture was cooled and ethanol was removed under reduced pressure. The piperazine formed as a white solid was dissolved in dichloromethane and was converted to its hydrochloride by the addition of con. HCI. The piperazine hydrochloride was separated, washed with dichloromethane and then was neutralized with aqueous ammonia to afford the piperazine. Recrystallization from ethanol yielded colourless crystals of 5, yield 1 .6 g (45%); m.p. 1 65-167°C; (Found: C, 83.96; H, 7.94; N, 7.6 1 . C2sH28N2 requires C, 84.23; H, 7.92; N, 7.86%); IR (KBr): 3300 crn'l (NH); lH NMR (CDCh): & 0.85 (3H, d, CH3), 1 .02 (3H, d, CH3), 1 .5 1 - 1 .53 ( l H, m, -CH(CH3)2), 1 .78 (2H, br, s, NHs), 2 .98 ( lH, dd, 1=9.38 and 2.34 Hz, H5), 3.83 ( I H, d, 1=8 .78 Hz, H2), 3.90 ( lH, d, 1=8.94 Hz, H3), 3 .94 ( I H, d, 1=9. 1 8 Hz, H6), 7. 1 1 -7.57 ppm ( I5H, m); l 3C NMR (CDCh): & 1 5 .7, 20.8 (CH3), 28.0 (CH-(CH3h), 64.6, 66.5, 68.6 (C2, C3, C5 and C6 carbons) 1 27 .1, 1 27.2, 1 27.5 , 1 27.6, 1 27.7, 1 28.2,

1 28 .3 , 1 28 .4 (aromatic carbons), 1 4 1 .7 , 142. 1 , 142.5 ppm (ipso carbons); MS: m1z 356 (M+).

t-5-Methyl-r-2,t-3, c-6-triphenylpiperazine 6. By following the procedure described for 5 the 5-methyl-2,3,6-triphenylpiperazine 6 was prepared from 5-methyl-2,3 ,6-triphenyl-5 ,6-dihydropyrazine (3.20 g, 0. 1 mole) by reduction with sodium borohydride. Yield 1 .70 g (52%); mp l 35-40°C (Found: C, 83.42; H, 7. 1 2; N, 8.60. C23HuN2 requires C, 83J)6; H, 7 .27;

. N, 8 .46%), IR (KBr): 33 1 0 cm,l (NIl); lH NMR(CDCh): & 0.95 (3H, d, 1=6.3 Hz, CH3), 1 .96 (2H, br, s, NHs), 3 . 1 2 ( I H, m, H5), 3 .69 ( l H, d, 1=8.7 Hz, H6), 3.95 (2H, s, H2 and H3), 7 . 1 1 -7.57 ppm ( 1 5H, m); l3C NMR (CDCh): & 19.0 (CH3), 57.9 (C5), 68.5, 68.8, 68 .83 (C6, C2 and C3 carbons) 1 27 .2, 1 27.3, 1 27.7, 1 27 .8, 1 27.9, 1 28 .2, 1 28.3, 1 28.4 (aromatic carbons), 1 4 1 .5 , 14 1 .6, 142.5 ppm (ipso carbons); MS: m1z 328 (M+).

NI,N4-Diformyl-5-isopropyl-2,3,6-triphenyJpiper­azine 9. To a cold solution of acetic anhydride (40 mL), 85% formic acid (20 mL) was added slowly. After the addition was over the solution was heated to 60°C and then maintained at 50-60°C for 1 .5 hr. Then the mixture was again cooled to 5°C and added dropwise to a cold solution of 5-isopropyl-2,3,6-triphenylpiperazine (3.56 g, 0.0 1 mole) in dry benzene (50 mL). The reaction mixture was stirred at 25°C for 24 hr and then poured into ice-cold water. The benzene layer was separated and the aqueous layer was extracted wjth ether. The solvents were removed at reduced pressure from the combined organic layer. The crude diformylpiperazine 9 was recrystallized from ethanol, yield 2.6 g (63%), mp 194-96°C (Found: C, 78.30; H, 6.94; N, 6.6 1 . C27H2sN202 requires C, 78.59; H, 6.84; N, 6.82%); IR (KBr): 1 650-80 (br) cm'l (C=O); IH NMR (CDCh): Rotamer A: & 1 .25 (d, 1=7.33 Hz, CH3), 1 .3 1 (d, 1=6.84 Hz, C1I3), 2. 1 7 (m, -CH(CH3)2), 4.95 (d, 1=1 1 .23 Hz, H2), 4.35 (d, 1=1 1 .23 Hz, H3), 4.93-5.00 (merged, H5), 6. 1 1 (s, H6); Rotamer B: & 1 . l 3 (d, 1=6 .35 Hz, CH3), 1 . 15 (d, 1=:6.35 Hz, CH3), 2.0 (m, -CH(CH3h), 5 .2 1 (d, 1=1 0.30 Hz, H2), 4.42 (d, 1=1 0.25 Hz, H3), 4.93-5.00 (merged, H5), 5. 17(s, H6); Rotamer C: & 1 .22 (d, 1=6.35 Hz, CH3), 1 . 10 (d, 1=6.34 Hz, CH3), 2.28 (m, -CH(CH3h), 5 .29 (d, 1=9.28 Hz, H2)� 5 . l 3 (d, 1=9.28 Hz, H3), 3 .7 1 (d, 1= 1 0.74 Hz, H5), 5.96(s, H6), Rotamer D: & 0.50 (d, 1=6.35 Hz, CH3), 0.92 (d, 1=6.84 Hz, CH3), 1 .8 (m, -CH(CH3h), 4.93-5.00 (merged, H2), 4.93-5.00 (merged, H3), 3 .83 (d, 1= 1 1 .23 Hz, H5), 6.45(s, H6),

834 INDIAN J CHEM, SEC B, NOVEMBER 2000

6.77-7.63 (m, aromatic protons corresponding to all the four rotamers), 8 .0 1 , 8 .02, 8 . 19, 8.28, 8.38, 8.46, 8 .50, 8 .63 (formyl protons).

I 3C NMR (CDCh):

Rotamer A*: 0 65.0 (C2), 62.9 (C3), 56. 1 (C5), 5 1 .4 (C6); Rotamer B: 0 56.0 (C2), 6 1 .6 (C3), 55.7 (C5), 6 1 . 1 (C6); Rotamer C: 0 6 1 .3 (C2), 59.4 (C3), 64.8 (C5), 53.0 (C6); Rotamer D: 0 5 1 .0 (C2), 52.4 (C3),

. 65 .4 (C5) ; 1 36.9, 1 37. 1 , 1 39.7 (ipso carbons), 125.6, 1 26. 1 , 1 26.3, 126.6, 1 27 .5, 1 27.9, 1 28.3, 128 .4, 1 28.6, 128.8 , 1 29.2 (aromatic carbons), 1 64.8, 165 .4 (formyl carbons); MS: mJz 4 1 2 (M+).

Nt, N4-Diformyl-5-metbyl-2, 3, 6-triphenylpipera­zine 10. B y following the procedure as described for 9, N1.N4-diformyl-5-methyl-2,3 ,6-triphenylpiperazine 10 was prepared from the 5-methyl-2,3,6-triphenylpiper­azine (3.28 g, 0 .01 mole); yield 2.4 g (62.5%), mp 148-50°C (Found: C, 77.82; H, 5 .94; N, 7.6 1 . C25H:uN202 requires C , 78.08 ; H , 6.29; N , 7.32%); IR (KBr): 1 660-85 (br) cm·1 (C=O); lH NMR (CDCh): 0

Rotamer A: 1 .67 (d, 1=6.83 Hz, CH3), 4.45 (d, 1=1 1 .23 Hz, H2), 4.99 (d, 1=1 1 .24 Hz, H3), 5 .44 (m, H5), 5 . 8 1 (s, H6); Rotamer B: 0 1 . 17 (d, 1=6.35 Hz, CH3), 5 .88 (d, 1=4.39 Hz, H2), 4.85 (d, 1=4.88 Hz, H3), 4.82 (m, H5), 4.43 (d, 1=8.78 Hz, H6); Rotamer C: 0 1 .60 (d, 1=6.83 Hz, CH3), 5 . 1 3 (d, 1=6.34 Hz, H2), 5.70 (d, 1=6.84 Hz, H3), 4.30 (m, H5), 5 .25 (d, 1=4.5 Hz); Rotamer D: 0 1 .09 (d, 1=6.35 Hz, CH3), 6.43 (s, H2), 4.09 (m, H5), 4.35 (d, 1=8.78 Hz, H6), 6.74-7.49 (m, aromatic protons), 7 .89, 7.92, 8 . 1 2, 8. 15 , 8 . 19, 8.28, 8 .32, 8.60 (formyl protons);

I 3C

NMR (CDCh): Rotamer A: 0 1 8.4 (CH3), 62.5 (C2), 65.0 (C3), 45.9 (C5), 54.6 (C6); Rotamer B: 0 20.9 (CH3), 58. 1 (C2), 6 1 . 1 (C3), 5 1 .2 (C5), 60.7 (C6); Rotamer C: 0 2 1 .9 (CH3), 59.5 (C3), 52.8 (C6); Rotamer D: 0 19 .8 (CH3), 53.0 (C2), 52.7 (C5), 62.2 (C6); 125.9, 1 26.3, 1 26.4, 1 26.6, 1 26.8, 1 26.9, 1 27.7, 127.8, 1 27.9, 128. 1 , 1 28 .2, 1 28 .3 , 128.5, 1 28.6, 128.7, 1 28.8, 128.9, 1 29.0, 1 29. 1 , 1 29.2, 1 29.4, 1 29.7, 129.8 (aromatic carbons corresponding to all the four rotamers), 1 36. 1 , 1 37 . 1 , 1 37 .2, 1 37.3, 1 37.6, 1 38. 1 , 1 39.0, 1 39.2, 1 39.4, 1 39.7 (ipso carbons), 162.8, 162.8, 1 63 .0, 1 63.5 , 1 63.6, 1 64. 1 , 1 64.3, 1 65 . 1 (formyl carbons); MS: mJz 384 (M+).

Nt,N4-Diformyl-5-methyl-2,3-diphenylpiperazine 11. The procedure described for 9 was followed to prepare the diformyl derivative of 5-mcthyl-2,3-di­pheny1piperazine (2.52 g, 0.01 mole). The difonnylpiper­azine 11 was recrystallized from ethanol, yield 2.2 g (70%), mp 155-56°C (Found: G, 73.76; I I, 6.84; N, 9.6 1 . Cl 9HwN202 requires C, 73.97; H, 6.53; N,

9. 12%); IR (KBr) : 1 670-90 (br) cm·1 (C=O); lH NMR (CDCh): Rotamer A: 0 1 . 16 (d, 1=6.5 1 Hz, CH3), 5 .03 (d, 1=2. 10 Hz, H2), 5 .56(d, 1;:::2.30 Hz, H3), 4.48 (m, H5), 3 .78 (dd, 1= 14.60, 6.00 Hz, H6eq), 3.48 (dd, 1= 14. 1 , 7 .9 Hz, H6ax); Rotamer B: 0 1 .00 (d, 1=6.90 Hz, CH3), 5 .60 (s, H2), 6.39 (s, H3), 3 .82-3.90 (merged, H5), 3 .82-3.90 (merged, H6eq), 3.09-3 .38 ( merged, H6ax); Rotamer C: 0 0.92 (d, 1=6.80 Hz, CH3), 6.30 (s, H2), 5 . 1 9 (s, H3), 4.63 (m, H5), 3.59 (dd, 1=1 3 .5 , 4.9 Hz, H6eq), 3 .09-3 .38 (merged, H6ax) ; Rotamer D: 0 0.85 (d, 1=7 , 10 Hz), 6.49 (s, H2), 6.55 (s, H3), 3 .82-3.90 (merged, H5), 3 .40 (dd, 1=1 3 .3, 4.3 Hz, H6eq), 3 .09-3.38 (merged, H6ax), 7.2 1 -7.96 (m, aromatic protons corresponding to all the four rotamers), 8.24-8.62 (formyl protons);

I 3C

NMR (CDCh): Rotamer A: 0 1 8.8 (CH3), 60.6 (C2), 58.7 (C3), 46.4 (C5), 40.5 (C6); Rotamer B: 0 1 8 . 1 (CH3), 5 1 .7 (C2), 58 .5 (C3), 45. 1 (C5), 45.4 (C6); Rotamer C: 8 2 1 . 1 (CH3), 56.6 (C2), 50.4 (C3), 49.4 (C5), 40.7 (C6); Rotamer D: 8 20.3 (CH3), 49.0 (C2), 49.5 (C3), 49.8 (C5), 46.0 (C6); 1 26.3, 126.33, 126.4, 1 26.8, 1 27 .03, 127.7, 1 27.8, 127 .97, 1 28 . 1 , 128.24, 1 28.3 , 1 28 .4, 128.5, 1 28.7, 1 28.8, 1 28.9, 1 29.0, 129. 1 , 1 29.2 (aromatic carbons); 1 36.9, 1 37.2, 1 37.5, 1 38.4, 1 38.9, 1 39.5, 140. 1 (ipso carbons), 1 62.2, 1 62.3, 1 62.5, 1 62.7, 1 62.8, 1 62.9, 163.3, 163.6 (formyl carbons); MS: mJz 308 (M+).

N., N4-Diformyl-r-2,t-3-diphenylpiperazine 12. The diformylpiperazine 12 was prepared from the 2,3-diphenylpiperazine by the reaction with acetic-formic anhydride by following the procedure described for 9. Yield 2.3 g (78%), mp 1 55-56°C. (Found: C, 7'3.76; H, 6.04; N, 9.6 1 . CisH 1SN202 requires C, 73.42; H, 6. 1 6; N, 9.55%). IR (KBr) 1 655-70 (br) cm· 1 (C=O); lH NMR (CDCh): Rotamer A: 8 3 . 1 7 (dt, 1= 1 2.30, 3 .49 Hz, H51H6) , 3.59 (d, 1=1 0.67 Hz, H51H6), 4.04 (m, H51H6), 4.70 (d, 1= 10.52 Hz, H51H6), 4.78 (d, 1=3.2 Hz, H21H3), 5 .65 (d, 1=3.2 Hz, H21H3); Rotainer B: 0 3 .74 (m, H51H6), 4.85 (s, H21H3); 6.94-7.36 (aromatic protons), 8.09, 8 . 1 0, 8 . 1 8 (fonny I protons) ;

I 3C NMR (CDCI3 in 0

ppm): 37.9, 40.6, 4 1 .7 (C5 and C6), 55.5, 63.8, 64.4 (C2 and C3), 1 28 .6, 1 28.8 , 1 28.9, 129.5, 1 30.0 (aromatic carbons), 1 34.6, 1 36.2 (ipso carbons), 1 60.8, 1 6 1 .7, 1 62.0 (formyl carbons); MS : rnIz 294 (M+).

Acknowledgement The authors thank DST and CSIR for research

grallt and Sophi sticated Instrumentation Facility,

lEY ARAMAN et al. : CONFORMATIONAL PREFERENCES OF N I ' N. - DIFORMYLPIPERAZINES 835

Indian Institute of Science, Bangalore and Regional Sophisticated Instrumentation Centre, Indian Institute of Technology, Chennai for service in recording the lH and l3C NMR spectra and Regional Sophisticated Instrumentation Centre, Central Drug Research Institute, Lucknow for mass spectra.

References 1 (a) Ravindran T, Jeyaraman R, Murray R W & Singh M, J

Org Chern, 56, 1991, 4833. (b) Sukumar N, Ponnuswamy M N, Thenmozhiyal J C & Jeyaraman R, Bull Chern Soc Jpn, 67, 1994, 1 069.

2 Jeyaraman R & Ponnuswamy S, Indian J Chern, 36B, 1997, 730.

3 (a) Jeyararnan R, Senthilkumar U P & Bigler P, J Org Chern, 60, 1995, 7461 . (b) Senthilkumar U P, Jeyararnan R , Murray R W & Singh M, J Org Chern, 57, 1992, 6006. (c) Jeyararnan R & Ponnuswamy S, J Org Chern, 62, 1997, 7984.

4 Jeyararnan R, Thenmozhiyal J C, Murugadoss R, Venkatraj M, Lavaanya P, Panchanatheswaran K & Bhadbhade M S, Indian J Chern, (in press).

5 (a) Gdaniec M, Milewska M J & Polonski T, J Org Chern, 60, 1995, 741 1 .

(b) Polonski T, Pham M & Milewska M J, J Org Chern, 6 1 , 1996, 3766.

6 (a) Lunazzi L, Cerioni G & Ingold K U, J Arn. Chern Soc, 98, 1976, 7484. (b) Lunazzi L, Cerioni G, Foresti E & Macciantelli 0, J Chern Soc, Perkin Trans-2, 1978, 686.

7 (a) Johnson R A, Chern Rev, 68, 1968, 375. (b) Fraser R R & Grindley T B, Tetrahedron Lett, 1974, 4 1 69 .

8 Baliah V & Pandiarajan K. Indian J Chern, 1 6B, 1978, 73. 9 Sato N & Adachi J, J Org Chern, 43, 1978; 341 .

1 0 (a) Hirsch J A, Augustine R L, Ko1etar G & Wolf H G, J Org Chern, 40, 1975, 3547. (b) Pinto M, Grindley T B & Szarek W A, Mag Res Chern, 24, 1986, 323.

1 1 Rubiralta M, Marco M P, Feliz M & Giralt E, Heterocycles,

29, 1989, 2 1 85 . 1 2 (a) Karplus M , J Chern Phys, 30, 1959, 1 1 .

(b) Karplus M, J Arn Chern Soc, 85, 1963, 2870. 13 Lavaanya P, Panchanatheswaran K, Murugadoss R &

Jeyaraman R, Acta Cryst, C55, 1999, 4 1 0. 14 (a) Dewar M J S, Zoebisch E G, Healy E F & Stewart J J p, J

Arn Chern Soc, 107, 1985, 3902 and related papers. (b) Stewart J J P, J Cornput Aided Mol Des, 4, 1990, I .

1 5 (a) Beugelmans R, Benadjila-Iguertsira L, Chastanet J, Negron G & Roussi G, Can J Chern, 63, 1985, 725. (b) Shono T, Kise N, Shirakawa E, Matsumoto H & Okazaki E, J Org Chern, 56, 1991, 3063.