Journal of Molecular Structure (Theo&em), 206 (1990) 29-38 Elsevier Science Publishers B.V., Amsterdam - Printed in The Netherlands

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AB INITIO STUDIES OF MOLECULES WITH N-C-O UNITS

Part 2.1-Oxa-3-azacyclohexane, 1-oxa-3,5-diazacyclohexane and 1,3-dioxa-5-azacyclohexane

LUGS CARBALLEIRA, BERTA FERNANDEZ and MIGUEL A. RIOS

Departamento de Quimica Fkica, Universidad de Santiago de Compostela, E-15706 Galicia (Spain)

(Received 26 May 1989)

ABSTRACT

Conformers of l-oxa-3-azacyclohexane, 1-oxa-3,5_diazacyclohexane and 1,3-dioxa-5-azacy- clohexane were studied by an ab initio method using the 4-21G basis set and complete geometrical optimization. The results were interpreted in terms of anomeric interactions, and the influence of the heteroatoms on ring planarity and the environments of the nitrogen atoms are discussed.

INTRODUCTION

One of the phenomena that accounts most for the properties of rings con- taining heteroatoms is the anomeric effect: polar bonds C-X with antibonding orbitals tend to be tram to an sp3 lone pair of a heteroatom adjacent to a carbon atom because of the interaction between the lone pair and the antibonding orbital [ 11. In general, this interaction affects the energy and reactivity of the molecule as well as its conformation.

In this article, we invoke the anomeric effect to explain the structural and energy trends predicted by ab initio 4-21G [2] calculations (Pulay’s method [ 31 and program [4] ) for the conformers of the heterocycles 1-oxa-3-azacy- clohexane (OAC), 1-oxa-3,Uiazacyclohexane (ODAC) and 1,3-dioxa-Saza- cyclohexane (DOAC); the influence of the number and nature of the hetero- atoms and the orientation of their substituents on the planarity of the ring. The environment of the N atoms is also discussed. The data obtained will subsequently be employed, together with those determined in Part 1 of this series of articles [ 51, to parametrize a molecular mechanics force field to be used in the study of more complex N-C-O compounds, such as certain impor- tant drugs.

The conformations of the compounds studied here, and their derivatives, have been the subject of several experimental studies. The predominance of

0166-1280/90/$03.50 0 1990 Elsevier Science Publishers B.V.

30

‘i 10

3 13 5 eif 14 4

0 12 1 9

15

2 6 OAC

8 ‘1.

10 14

6 ODAC

11

9 11

2 10 DOAC

8

Fig. 1. The atom numbering used for I-oxa-3-azacyclohexane (OAC ), l-oxa-3,5-diazacyclohexane (ODAC) and 1,3-dioxa-5-azacyclohexane (DOAC).

the axial conformer of OAC has been confirmed by ‘H-NMR [ 61 and infrared (IR) spectroscopy [ 71 and by dipole-moment measurements [ 81, but the ex- perimental findings for derivatives of OAC have been contradictory [ 91.

The most stable conformer of the N&V-dimethyl derivative of ODAC has one axial and one equatorial methyl group and both ‘H-NMR and i3C-NMR stud- ies have shown the most stable conformer of N-methyl DOAC to be that in which the methyl is axial [lo].

In the theoretical study described here, geometries were optimized with no constraints other than those imposed by symmetry until the Cartesian com- ponents of the forces on the atoms were all less than 0.001 mdyn. Optimization began starting from all the possible chair conformations, i.e. the OAC and DOAC conformations with the nitrogen H axial (A) and equatorial (E ) and the ODAC conformations with both the nitrogen H atoms axial (AA), both equatorial (EE), and one axial and one equatorial (AE). The atom numbering of the molecules is shown in Fig. 1.

RESULTS AND DISCUSSION

1 -Oxa-3-azacyclohexane (OAC)

The geometries and absolute and relative energies of the two OAC conform- ers are listed in Table 1. In agreement with the experimental findings, the axial

31

TABLE 1

Geometries and absolute and relative energies of the conformers of 1-oxa-3-azacyclohexane (OAC)

Conformer Conformer

A E A E

Bond length

(A) c2-01 N3-C2 C4-N3 C&C4 C6-01 C6-C5 H7-N3 H8-C2 HS-C4 HlO-C5 Hll-C6 H12-C2 H13-C4 H14-C5 H15-C6

Bond angks (“) N3-C2-01 C4-N3-C2 C5-C4-N3 C6-Ol-C2 C6-C5-C4 C5-C6-01 H7-N3-C2 H7-N3-C4 H8-C2-01 H8-C2-N3 HS-C4-N3 HS-C4-C5 H10-C5-C4 HlO-C5-C6 Hll-C6-01 Hll-C6-C5 H12-C2-01 Hl2-C2-N3 H12-C2-H8 Hl3-C4-N3 H13-C4-C5 H13-C4-HS H14-C5-C4 H14-C5-C6 H14-C5-HlO H15-C6-01 H15-C6-C5 H15-C6-Hll

1.4492 1.4366 1.4504 1.4575 1.4805 1.4706 1.5434 1.5382 1.4499 1.4499 1.5378 1.5345 1.0033 0.9998 1.0828 1.0915 1.0835 1.0916 1.0829 1.0800 1.0865 1.0865 1.0763 1.0773 1.0806 1.0808 1.0835 1.0833 1.0786 1.0783

112.96 110.30 112.22 113.74 111.16 107.41 112.18 112.54 109.39 109.62 110.38 110.34 111.79 113.96 111.63 114.99 109.14 108.31 108.39 112.21 107.66 112.34 109.82 109.53 109.37 108.48 108.86 108.90 109.56 109.54 109.97 110.20 106.02 106.58 110.34 109.77 109.97 109.49 108.83 108.89 111.40 110.52 107.84 108.16 110.87 110.69 109.99 109.89 108.33 109.23 106.18 105.86 111.81 111.83 108.85 108.96

Torsional angles (“) N3-C2-Ol-C6 H8-C2-Ol-C6 H12-C2-Ol-C6 C4-N3-C2-01 H7-N3-C2-01 C4-N3-C2-H8 H7-N3-C2-H8 C4-N3-C2-H12 H7-N3-C2-H12 C5-C4-N3-C2 C5-C4-N3-H7 HS-C4-N3-C2 HS-C4-N3-H7 H13-C4-N3-C2 H13-C4-N3-H7 C6-C5-C4-N3 C6-C5-C4-HS HlO-C5-C4-N3 HlO-C5-C4-HS C6-C5-C4-H13 HlO-C5-C4-H13 H14-C5-C4-N3 H14-C5-C4-HS H14-C5-C4-H13 C5-C6-Ol-C2 Hll-C6-Ol-C2 H15-C6-Ol-C2 Ol-C6-C5-C4 Ol-C6-C5-H10 Hll-C6-C5-C4 Hll-C6-C5-HlO Ol-C6-C5-H14 Hll-C6-C5-H14 H15-C6-C5-C4 H15-C6-C5-HlO H15-C6-C5-H14

Energies &al mol -*)

Absolute Relative

57.96 57.54 -62.68 -65.62 178.92 176.65 -55.03 - 59.08 71.28 166.45 66.03 61.78 - 167.66 - 72.69 - 173.50 - 176.23 -47.19 49.30 52.60 57.72 - 73.79 - 168.29 -67.72 - 62.79 165.89 71.20 175.65 177.53 49.25 - 48.59 -52.11 -54.80 66.93 67.47 67.03 63.99 - 173.93 - 173.74 - 173.67 - 173.47 -54.53 -54.67 - 173.58 - 176.18 -54.54 -53.91 64.86 65.16 -57.51 -57.15 63.74 64.34 - 178.88 - 178.32 54.48 55.70 - 64.97 - 62.83 -66.51 -65.39 174.03 176.07 176.48 177.56 55.49 56.46 172.44 173.25 52.99 54.71 - 65.56 - 64.90

- 179073.80 0.00

- 179069.05 4.75

32

TABLE 2

Ring-puckering coordinates (8, 8, @) [ 111 and N environment planarities (h) of OAC, 1,3- diazacyclohexane (DACH) [ 12 ],1,3,5triazacyclohexane (TACH) [ 121, ODAC and DOAC

Conformer

OACA 0.546 -2.9 121.7 0.3691 OACE 0.568 - 1.9 24.4 0.3089

DACHAA 0.527 3.1 120.0 0.3705 0.3705 DACHAE 0.566 3.4 22.4 0.3971 0.3449 DACHEE 0.584 1.8 120.0 0.3438 0.3438

TACHAAA 0.500 0.0 60.3 0.3741 0.3741 0.3741 TACHAAE 0.543 4.9 0.0 0.3967 0.3967 0.3452 TACHAEE 0.561 1.1 120.0 0.4200 0.3362 0.3362 TACHEEE 0.561 0.0 0.0 0.3416 0.3416 0.3416

ODACAA 0.519 -3.0 180.0 0.3745 0.3745 ODACAE 0.543 -2.0 28.4 0.4001 0.3085 ODACEE 0.542 -0.3 180.0 0.2976 0.2976

DOACA 0.522 -0.4 60.0 0.3764

conformer, A, in which the N lone pair is anti to the C-O bond, is 4.75 kcal mol-’ more stable than the equatorial conformer, E, in which the N lone pair is anti to less polar C-H bonds. The anomeric effect likewise accounts for the following structural trends.

(i) The C4-C5 and C2-0 bonds are longer in A, in which they are anti to the N lone pair, than in E.

(ii) Again because of orientation with respect to the N lone pair, the C-H8 and C-H9 bonds are longer in E than in A (1.0915 and 1.0916 A, respectively, versus 1.0828 and 1.0835 A).

(iii) The angle N-C-C is wider in A than in E (111.16” versus 107.41” )

because in A C4-C5 is truns to the N lone pair. (iv) Again because of the N lone pair, N-C-H8 and N-C-H9 are wider in E

than in A (112.21” and 112.34”, respectively, versus 108.39” and 107.66”). In E, these angles are wider than N-C-H12 and N-C-H13, which are not subject to the anomeric effect.

(v) The oxygen lone pairs make O-C6-H,, wider than O-C6-H,, in both conformers.

(vi) Because of the influence of the N lone pair, N-C-O is wider in A than in E (112.96” versus 110.30”).

The calculated ring-puckering coordinates [ 111 (Table 2 ) show A to have a

33

flatter ring than E. The values of 8 show both A and E to be almost perfect chairs. In E, the environment of the N atom is flatter (i.e. the distance from N to the plane defined by the three atoms bound to it is less) than in A.

1 -Oxa-3,5_diazacyclohexane (ODAC)

The geometries and energies of the three ODAC conformers are listed in Table 3. The anomeric effect satisfactorily explains why the most stable form is AA; the size of the methyl groups account for the experimental finding that the most stable N,N-dimethyl ODAC conformer is not AA but AE. The struc- tural consequences of the anomeric interactions present may be summarized as follows.

(i) Equatorial C-H bonds are shorter than axial ones because they are not subject to anomeric interactions. Among the axial C-H bonds, C-H11 is longer in AE and EE than in AA (1.0912,1.0920 and 1.0827 A, respectively) because in AE and EE it is anti to the N5 lone pair, and C-H11 is longer than C-H9 in AE for the same reason. C-H9 is longest in the only conformer in which it is tram to the N3 lone pair, i.e. EE.

Where two different anomeric interactions occur, their effects are cumula- tive: C-HlO, for example, is longest in EE, in which it is tram to both the nitrogen lone pairs; shortest in AA, in which it is tram to neither; and has an intermediate length in AE, in which it is tram to one of the N5 lone pair but not to the N3 one.

(ii) C4-N5 is longer in AA and AE than EE (1.4755 and 1.4706 A, respec- tively, versus 1.4646 A) because in AA and AE it is trans to the N3 lone pair; for the same reason, in AE C4-N5 is longer than C4-N3. C4-N3 is longest in AA, in which it is anti to the N5 lone pair.

(iii) C2-0 is longer in AA and AE than in EE owing to the effect of N3 in AA and AE. In AE, C2-0 is longer than C6-0 for the same reason. C6-0 is longest in AA, in which it is tram to the N5 lone pair (1.4515 A in AA versus 1.4398 A in AE and 1.4388 A in EE).

(iv) O-C-H,, angles are wider than O-C-H,, angles because of the oxygen lone pairs.

(v) The angle N-C-N also exhibits the cumulation of anomeric interac- tions, being widest in AA, in which both N lone pairs are involved, narrowest in EE, in which neither is involved, and intermediate in AE, in which just one pair is involved.

(vi) O-C-N5 is widest in AA (112.48” versus 109.94” in AE and 109.99” in EE) because of the anomeric effect of N5. Analogously, O-C-N3 is wider in AA and AE than in EE because of the effect of N3. In AE, O-C-N3, which is influenced by the lone pair of N3, is wider than O-C-N5, which suffers no N anomeric effect.

(vii) The N-C-H,, angles are wider than N-C-H,, angles that are not in-

34

TABLE 3

Geometries and absolute and relative energies of conformers of 1-oxa-3,Sdiazacyclohexane (ODAC)

Conformer

AA AB EE

Bond lengths (A) c2-01 N3-C2 C4-N3 N5-C4 C6-01 C6-N5 H7-N3 HE-N5 H9-C2 HlO-C4 Hll-C6 H12-C2 H13-C4 H14-C6

Bond angles (“) N3-C2-01 C4-N3-C2 N5-C4-N3 C6-Gl-C2 C6-N&C4 N5-C6-01 H7-N3-C2 H7-N3-C4 HS-N5-C4 HS-N5-C6 H9-C2-01 H9-C2-N3 HIO-C4-N3 HlO-C4-N5 Hll-C6-01 Hll-C6-N5 H12-C2-01 H12-C2-N3 H12-C2-H9 H13-C4-N3 H13-C4-N5 H13-C4-HlO H14-C6-01 H14-C6-N5 H14-C6-HI 1

1.4515 1.4511 1.4388 1.4565 1.4548 1.4562 1.4755 1.4699 1.4646 1.4755 1.4706 1.4646 1.4515 1.4398 1.4388 1.4565 1.4628 1.4562 1.0036 1.0042 0.9989 1.0036 1.0001 0.9989 1.0827 1.0827 1.0920 1.0804 1.0878 1.0971 1.0827 1.0912 1.0920 1.0760 1.0755 1.0765 1.0780 1.0783 1.0789 1.0760 1.0769 1.0765

112.48 112.43 109.99 111.25 111.02 113.78 113.05 109.09 107.25 111.26 112.02 111.99 111.25 112.70 113.78 112.48 109.94 109.99 111.69 110.59 114.89 111.97 109.86 115.16 111.97 115.62 115.16 111.69 114.40 114.89 109.10 109.30 108.11 108.24 108.40 112.35 107.79 107.27 111.31 107.79 112.47 111.31 109.10 108.29 108.11 108.24 112.04 112.35 106.45 106.05 106.69 110.61 110.53 109.94 109.94 110.11 109.59 109.66 109.55 109.16 109.66 109.55 109.16 108.79 108.85 108.62 106.45 106.86 106.69 110.61 110.02 109.94 109.94 109.54 109.59

35

Conformer

AA AE EE

Torsional angles (“j N3-C2-Ol-C6 H9-C2-Ol-C6 H12-C2-Ol-C6 C4-N3-C2-01 H7-N3-C2-01 C4-N3-C2-H9 H7-N3-C2-H9 C4-N3-C2-H12 H7-N3-C2-H12 N5-C4-N3-C2 N5-C4-N3-H7 HlO-C4-N3-C2 HlO-C4-N3-H7 H13-C4-N3-C2 H13-C4-N3-H7 C6-N5-C4-N3 H8-N5-C4-N3 C6-N5-C4-HlO H8-N5-C4-HlO C6-N5-C4-H13 H8-N5-C4-H13 N5-C6-Ol-C2 Hll-C6-Ol-C2 H14-C6-Ol-C2 Ol-C6-N5-C4 Ol-C6-N5-H8 Hll-C6-N5-C4 Hll-C6-N5-H8 H14-C6-N5-C4 H14-C6-N5-H8

Energies &al mol - ‘) Absolute Relative

55.60 55.14 56.17 -64.32 - 65.28 -66.84 177.09 176.04 175.36 -53.17 -55.14 - 56.54 72.74 67.08 167.68 67.45 65.80 63.93 -66.64 - 171.98 -71.84 - 172.05 - 173.43 - 173.74 -46.13 -51.21 50.48 50.84 54.88 54.47 - 74.92 - 67.76 - 169.87

-68.19 -67.21 - 67.50 166.05 170.15 68.16 173.53 174.79 172.61 47.77 52.15 -51.73 - 50.84 - 56.67 - 54.47 74.92 169.13 169.87 68.19 62.23 67.50 - 166.05 - 71.97 -68.16 - 173.53 - 176.58 - 172.61 -47.77 49.22 51.73 - 55.80 - 54.55 -56.17 64.32 68.16 66.84 - 177.09 - 173.92 - 175.36 53.17 56.60 56.54 -72.74 - 168.62 - 167.68 - 67.45 - 63.87 - 63.93 166.64 70.91 71.84 172.05 174.02 173.74 46.13 -51.20 - 50.48

- 189076.46 0.00

- 189070.98 5.48

- 189061.37 15.09

36

TABLE 4

Geometry and absolute energy of the single conformer of 1,3-dioxa-5-azacyclohexane (DOAC)

Bond lengths (A) cz-01 03-C2 c4-03 N5-C4 C6-01 C6-N5 H7-N5 H&C2 H9-C4 HlO-C6 Hll-C2 H12-C4 H13-C6

Bond angles (“) 03-C2-01 C4-03-C2 N5-C4-03 C6-Ol-C2 C6-N5-C4 N5-C6-01 H7-N5-C4 H7-N5-C6 H8-C2-01 H8-C2-03 H9-C4-03 H9-C4-N5 HlO-C6-01 HlO-C6-N5 Hll-C2-01 Hll-C2-03 Hll-C2-H8 H12-C4-03 H12-C4-N5 H12-C4-H9 H13-C6-01 H13-C6-N5 H13-C6-HlO

1.4328 1.4328 1.4525 1.4552 1.4525 1.4552 1.0030 1.0854 1.0823 1.0823 1.0736 1.0748 1.0748

111.96 112.05 111.54 112.05 111.15 111.54 111.65 111.65 109.43 109.43 109.24 108.55 109.24 108.55 107.46 107.46 111.09 106.39 110.86 110.25 106.39 110.86 110.25

Torsional angles (“) 03-C2-Ol-C6 H8-C2-Ol-C6 Hll-C2-Ol-C6 C4-03-C2-01 C4-03-C2-H8 C4-03-C2-Hll N5-C4-03-C2 H9-C4-03-C2 H12-C4-03-C2 C6-N5-C4-03 H7-N5-C4-03 C6-N5-C4-H9 H7-N5-C4-H9 C6-N5-C4-H12 H7-N5-C4-H12 N5-C6-Ol-C2 HlO-C6-Ol-C2 H13-C6-Ol-C2 Ol-C6-N5-C4 Ol-C6-N5-H7 HlO-C6-N5-C4 HlO-C6-N5-H7 H13-C6-N5-C4 H13-C6-N5-H7

Energy (kcal mol-‘)

- 54.34 67.17 - 172.11 54.34 -67.17 172.11 -54.13 65.87 - 175.13 53.65 - 71.74 -66.76 167.85 172.01 46.62 54.13 - 65.87 175.13 - 53.65 71.74 66.76 - 167.85 - 172.01 - 46.62

- 201485.20

volved in anomeric interactions. Among the N-C-H,, angles, N3-C-H10 is widest in EE because of the effect of N3, and N&C-H10 is wider in AE and EE than in AA because of the effect of N5. For the same reason, N&C-H10 is wider than N3-C-H10 in AE. Similar behaviour is exhibited by the angles N- C-H9 and N-C-Hll.

37

Like the OAC ring, the ODAC ring is most planar for the most axial con- former (AA) ; AE and EE have very similar Q values (Table 2). The near-zero values of 8 again show that all the chair conformers are almost perfect chairs. The N environments are again most planar in the conformer with most equa- torial N-H bonds.

1,3-Diora-5-azacycbhexane (DOAC)

In agreement with the experimental findings for N-methyl DOAC, the only DOAC conformer converged on was A, the energy and geometry of which are listed in Table 4. Again, this may be attributed to anomeric interactions, since the N lone pair is anti to both C4-03 and C6-01, which are very much more polar than the C-H bonds to which it is anti in conformation E. In E, moreover, there is the same strong mutual repulsion among three axial lone pairs as in the least stable ODAC conformer, EE, in which it is responsible for twisting the H atoms about 10” from the ideal equatorial conformation. The tri-equa- torial, 1,3,5triazacyclohexane conformer detected by 4-21G//4-21G calcula- tions [12] is likewise severely deformed and much less stable than other conformers.

DOAC conformer A also exhibits geometrical anomeric interactions: equa- torial C-H bonds are shorter than axial ones because of the effect of the oxygen atoms in the latter; the longest axial C-H bond is C-H& which is tram to two lone pairs, one on each oxygen atom; and O-C-H,, angles are wider than O- C-H,, angles, again because of the oxygen lone pairs. The puckering coordi- nates (Table 2) show that DOAC is an almost perfect chair.

Planarity trends

The present results, together with those of an earlier study [ 121 of 1,3-dia- zacyclohexane (DACH) and 1,3,5-triazacyclohexane (TACH), show that: (i) for rings with two or three heteroatoms the ring-puckering parameter, Q, de- creases as the number of N atoms with axial bonds increases; (ii) rings with three heteroatoms are flatter than those with two when the heteroatoms com- mon to both have similarly oriented bonds: and (iii) for the conformers with all N-H bonds equatorial, replacement of one N atom by an oxygen atom flat- tens the environment of the remaining N atom or atoms.

ACKNOWLEDGEMENTS

This work was supported by the Xunta de Galicia and through the award of an F.P.I. grant to B.F.

38

REFERENCES

1

6 I

a

9

10

11 12

C. Van Alsenoy, L. Schaefer, J.O. Williams, J.N. Scarsdale and H.J. Geise, J. Mol. Struct. (Theochem), 76 (1981) 349. P. Pulay, G. Fogarasi, F. Pang and J.E. Boggs, J. Am. Chem. Sot., 101 (1979) 2550. P. Pulay, Mol. Phys., 17 (1969) 197. P. Pulay, Theor. Chim. Acta, 50 (1979) 299. L. Carballeira, B. Ferna’ndez, R.A. Mosquera and M.A. Rios, J. Mol. Struct. (Theochem), 205 (1990) 235. H. Booth and R.U. Lemieux, Can. J. Chem., 49 (1971) 777. R.A.Y. Jones, A.R. Katritzky, A.C. Richards, S. Saba, A.J. Sparrow and D.L. Trepanier, Chem. Commun., (1972) 673. A.R. Katritzky, M. Moreno-Mafias, A.C. Richards, A.J. Sparrow and D.L. Trepanier, J. Chem. Sot., Perkin Trans II, (1973) 325. A.R. Katritzky, V.J. Baker and F.M.S. Brito-Palma, J. Chem. Sot., Perkin Trans. II, (1980) 1739. V.J. Baker, I.J. Ferguson, A.R. Katritzky, R.C. Pate1 and S. Rahimi-Rastgoo, J. Chem. Sot., Perkin Trans. II, (1978) 377. D. Cremer and J.A. Pople, J. Am. Chem. Sot., 97 (1975) 1354. L. Carballeira, B. Fernandez, R.A. Mosquera, J. Rodriguez, S.A. VQzquez and C. Van Alsenoy, J. Mol. Struct. (Theochem), 205 (1990) 223.