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Methylenebis-chlorophenols: Theoretical and experimental conformational analyses
136 (1986) 147-153 Elsevier Science Publishers B.V., Amsterdam - Printed in The Netherlands
Journal of Molecular Structure (Theochem),
METHYLENEBIS-CHLOROPHENOLS: THEORETICAL EXPERIMENTAL CONFORMATIONAL ANALYSES
S. RANTSORDAS*,
AND
J. ROYER and B. TINLAND
Laboratoire de Min&mlogie-cristallogmphie, U.A. 805 du C.N.R.S., Universitk Claude Bernard LYON I, 43, Bd du 11 Novembre 1918, 69622 Villeurbanne Cedex (Fmnce) (Received 5 June 1985)
ABSTRACT Force field calculations have provided information on the way in which conformations and strain energies of methylenebischlorophenols change as a function of substituent size and position. Comparisons are made with results obtained by X-ray diffraction methods. INTRODUCTION
In recent years, we have compiled crystallographic data on biologically active phenolic compounds [I]. Even though X-ray crystal structure investigations provide information on molecular geometry, this analysis of conformationally flexible molecules does not necessarily lead to the preferential conformations in solution or in isolated state. This is of crucial importance in biological compounds because their activity is intimately related to their conformation. This problem has been addressed in the literature [2] : spectroscopic and theoretical methods have been employed to investigate and compare the conformations in solution or in the isolated state with those obtained from the solid state. In this paper X-ray analysis conformations of methylenebis-phenols are compared with those given by the molecular mechanics method [3]. This method assembles, as a system of particles held together by forces and energy, a molecule described by a set of classical equations of motion which are functions of the atomic positions. These atomic positions are refined until a minimum energy geometry is found. Thus molecular mechanics can be used to test if the features observed in crystal structure are an inherent property of the molecule or the results of the way in which the molecule is influenced by its neighbours in the crystal. RESULTS
In the present work calculations of conformational minima energies were performed for a series of three methylenebis-chlorophenols containing 0166-1280/86/$03.50
0 1986 Elsevier Science Publishers B.V.
148
R5
R15
Fig. 1. Atomic numbering of the methylenebischlorophenol
molecule.
patterns of substitution. Figure 1 shows the adopted notation and Fig. 2 shows the molecular structure of the three compounds. Table 1 gives calculated and experimental values for the dihedral angle 0 between the two aromatic rings, eA and eB respectively between the benzene ring (A or B) and the plane containing CAY- C(H,) bonds, that, is, CZ-CZ1 and Cl* -CZ1, and the torsion angles (7 and 7’) around these bonds. different
DISCUSSION
In ternal angle deformations When H atoms in a benzene molecule are replaced by various atoms or functional groups, changes may result in the electron-withdrawing or releasing properties of the ring and this substitution is known to induce distortions (bond length variations and angular deformations) of the C hexagon from the perfect D 6h symmetry. Angular deformations are the most suitable parameters for the quantitative assessment, of the effect of the different substituents on the geometry of the ring [4]. The crystallographic data are reported in Table 2, and Table 3 gives the angle values obtained by X-ray analysis and FF calculations. It is worth noting here that the internal ring angle of the C carrying the hydroxyl and the chlorine atom is always greater than the ideal value of 120”; on the other hand, it is less than 120” for the C bearing the alkyl group as determined by X-ray analysis [l], which is also supported by calculations.
149
BIFCMT A RX
BIPCNT RX
BIPCNT
13.2 KCAL
BIFCTV 17.1 KCAL
Fig. 2. (a) Compound
WCMT
B RX
BIFCNT 15.5 KCAL
BIPCTV
17 7 KCAL
Ia: BIPCNT;
(b) compound lb
: BIPCMT; (c) compound
1~:
BIWTV.
131-O(5) -67.7(6) 84.4 129 65.3
122.8 133.7 80.6 58 46
122.8 -65 85.8 58 65
-119(2) 75(2) 100 119 76
mol. Q
[13.21a
[15.5]
Exper.c
Theor. mol. p -115(2) 75(2) 102 116 73
BIF’CMT (Ib)
-140 60.6 80 40 61.7
l-121
Theor.
-140 240 81 40 61.4
1151 -100.7(4) 76.9(4) 107.1 100.3 77.7
Exper.d
BIPCW
(Ic)
-103.5 -108 104.5 77.4 72.8
[17.1]
Theor.
-103.5 72 104.4 77.4 72.9
[17.7]
aThe bracketed number is the minimum energy in kcal mol -I . bRef. la. ‘Ref. lb. %f. lc. QTorsion angle C, Cl C,, Cl,, . ?I’orsion angle C,,C, C,,C,. aDihedral angle between planes A and B. hDihedraI angle between planes (C, C,, C,, ) and A. IDihedral angle between planes (C, C,, C,, ) and B.
P ?‘f es s.? @$
Exper.b
BIPCNT (Ia)
Minimum energies and experimental conformations
TABLE 1
151 TABLE 2 Crystallographic data
Space group a (esd) (A) S(A) c(A) 01(deg.) P (deg.) 7 (deg.) z
BIPCNT (Ia) Monoclinic’
BIPCMT (Ib) Crthorhombicb
BIPCTV (Ic) MonoclinicC
P2,lc
p21212,
P2, In
11.977(2) 19.035(3) 9.244(4) 90 109.25( 2) 90 4
3.972(l) 17.593(2) 90 90 90 6 (two molecules (Y and fl in asymmetric unit). 0.057
0.056
R (usual)
12.915(4) 9.157(4) 17.566(3) 90 105.22(3) 90 4
25.284(3)
0.043
aRef. la. bRef. lb. CRef. lc. TABLE 3 Internal benzene ring angles at the carbon atoms bonded to the substituents and central bond angle Substituents
BIPCNT (Ia) Exp .O
BIPCTV (Ic)
BIPCMT (Ib)
Theor.
Ex~.~ Molecule (a)
Molecule (0)
Theor.
Ex~.~
Theor.
OH
123.5(4) 123.9(4)
123.9 123.3
121.9(1.S) 123.3(1.4)
124.1(1.5) 124.1(1.5)
122.4 122.3
122.3(3) 123.1(3)
124.1 123.9
Cl
123.3(S) 121.9(4)
120.9 120.3
124.0(1.6) 125.8(1.5)
125.8(1.6) 123.6(1.5)
1213 121.9
122.7(3) 123.2(3)
121.3 121.2
CH,
117.6(4) 119.3(4)
117.7 113.0
120.9(1.S) 115.8(1.4)
115.6(1.5) 116.6(1.5)
120. 120.
116.4(3) 117.5(3)
119.3 119.3
CH-_(CH, ),
;;;‘$;
115.0 115.3
116.1(1.6) llS.l(l.4)
116.7(1.S) 116.1(1.4)
117.3 117.2
116.3(3) 113.6(3)
117.2 117.4
CH,
117.8(3) 117.0(4)
119.6 119.3
llS.l(l.4) 119.7(1.4)
116.7(1.5) 116.2(1.4)
117.6 117.6
118.4(3) 117.2(3)
117.3 117.3
C*-G-C,,
11&X6(4)
112.1
llS.g(l.3)
116.5(1.4)
113.2
112.1(3)
109.
aRef. la. bRef. lb. cRef. lc.
152
Dihedral angles
They are two minimum energy conformations for each compound: the second one is generated by freezing one phenol ring on this absolute minimum energy and rotating the second phenol ring around its Ch-CH, axis. Free rotations of the benzene rings around C-C,, and C,,-C,, axes are restricted by the ortho substituents: methyl and hydroxyl groups for BIPCNT (Ia) and BIPCMT (Ib), and the hydroxyl group only for BIPCTV (1~). The two conformations obtained are related by an approximate rotation of 180” of the second phenol ring around the Ch-CH2 axis and separated by higher rotational barriers for BIPCNT (280.5 kcal mol-‘) and BIPCMT (529.0 kcal mol-’ ) than for BIPCTV (25.8 kcal mol-’ ). Methylenebisphenols, in the neighbourhood of the calculated minimum energy, also possess a certain rotational freedom.
(a) BIPCNT
1500
(b)
BIPCMT
1000 1000
100 0 :-\.. Om 60,ml~,
B;20z0
360
T’
( c I BIPCTV 50.
IO_ : 0m60,m140,B~20~O0 r’
Fig. 3. Energy of the molecule: E = f (7’).
360
153
The dihedral angles between the two rings A and B are the same in the crystal state and the isolated molecule for the three compounds. The experimental and calculated conformations show a slight discrepancy for 0~ or 6s dihedral angles. Compounds Ia and Ic adopt, approximately, the second minimum energy. Intramolecular OH 0 hydrogen bonds (compounds Ia: 3.05 A. [la] ; Ib; 2.76 W and 2.71 A [lb] ; and Ic: 2.82 A [lc]) may control the conformation in the solid state. The molecules are all helical with 0~ or for experimental and = 40-80” for calculated conformations. OB = 50-80” In the crystal structure the valence angle C-C-C at the bridging group, Czl, is always different from the tetrahedral value and varies widely in the range 112-120”: BIPCNT 118.6” [4], BIPCMT 116” [l], and BIPCTV 112.1” [3]. The Calculation yields values of: BIPCNT 112.1”, BIPCMT 113.2”, and BIPCTV 109”. At the minimum energy level, the valence angle C-C-C at Co1 can be increased to the value found in the crystal structure by increasing the energy by ca. 0.8 kcal mol-’ (BIPCNT), 0.3 kcal mol-’ (BIPCMT), and 0.1 kcal mol-’ (BIPCTV). l
l
l
CONCLUSION
Since the energy barriers separating the two energy minima (Fig. 3) are high, conformational energy calculations indicate that two conformers could possibly be relevant to drug-receptor interactions. Of course knowledge of the interactions of drug molecules with the receptor is crucial in the understanding of the pharmacological features of this series of compounds. It should be emphasized that this analysis examines only the intrinsic conformational tendencies and the number of conformers of the molecule and yields nothing more than an inventory of possible or impossible conformations (or configurations). REFERENCES 1
(a) S. Rantsordas, M. Perrin and A. Thozet, Acta Crystaiiogr., Sect. B, 34 (1978) 1198. (b) S. Rantsordas, M. Perrin, A. Thozet and S. Lecocq, Acta Crystallogr., Sect. B, 37 (1981) 1253. (c)S. Rantsordas and M. Perrin, Acta Crystahogr., Sect. B, 38 (1982) 1871. (d) F. Nowshad and Mazhar-ul-Haque, J. Chem. Sot. Perkin Trans. 2: (1976) 623. (e) D. G. Hay and M. F. Mackay, Acta Crystallogr., Sect. B, 35 (1979) 2952. D. G. Hay, P. de Munk and M. F. Mackay, Au&. J. C&em., 33 (1980) 77, 34 (1981) 559. 2 (a) S. R. Byrn, C. W. Graber, and S. L. Midland, J. Org. Chem., 41 (1976) 2283. (b) J. Eckhardt and J. Bernstein, J. Am. Chem. Sot., 94 (1972) 3247. (c)R. M. Tel and J. B. F. N. Engberts, J. Chem. Sot., Perkin Trans. 2: (1976) 483. (d) J. Caillet, P. Claverie, and B. Pullman, Acta Crystallogr., Sect. B, 32 (1976) 2740. 3 (a) F. H. Westheimer, in M. A. Newman (Ed.), Steric Effects in Organic Chemistry, Wiley, New York, 1956, Chap. 12. (b) J. E. Williams, P. J. Stang and P. Von R. Schleyer, Ann. .Rev. Phys. Chem. 19 (1968) 531. (c) In this work we have used the MM, method: N. L. Allinger, J. Am. Chem. Sot., 99 (1977) 8127. 4 (a) A. Domenicano and P. Murray-Rust, Tetrahedron Lett., 24 (1979) 2283. (b) R. Norrestan and L. Schepper, Acta Chem. Stand. Ser. A, 35 (1981) 91.
Journal of Molecular Structure (Theochem),
METHYLENEBIS-CHLOROPHENOLS: THEORETICAL EXPERIMENTAL CONFORMATIONAL ANALYSES
S. RANTSORDAS*,
AND
J. ROYER and B. TINLAND
Laboratoire de Min&mlogie-cristallogmphie, U.A. 805 du C.N.R.S., Universitk Claude Bernard LYON I, 43, Bd du 11 Novembre 1918, 69622 Villeurbanne Cedex (Fmnce) (Received 5 June 1985)
ABSTRACT Force field calculations have provided information on the way in which conformations and strain energies of methylenebischlorophenols change as a function of substituent size and position. Comparisons are made with results obtained by X-ray diffraction methods. INTRODUCTION
In recent years, we have compiled crystallographic data on biologically active phenolic compounds [I]. Even though X-ray crystal structure investigations provide information on molecular geometry, this analysis of conformationally flexible molecules does not necessarily lead to the preferential conformations in solution or in isolated state. This is of crucial importance in biological compounds because their activity is intimately related to their conformation. This problem has been addressed in the literature [2] : spectroscopic and theoretical methods have been employed to investigate and compare the conformations in solution or in the isolated state with those obtained from the solid state. In this paper X-ray analysis conformations of methylenebis-phenols are compared with those given by the molecular mechanics method [3]. This method assembles, as a system of particles held together by forces and energy, a molecule described by a set of classical equations of motion which are functions of the atomic positions. These atomic positions are refined until a minimum energy geometry is found. Thus molecular mechanics can be used to test if the features observed in crystal structure are an inherent property of the molecule or the results of the way in which the molecule is influenced by its neighbours in the crystal. RESULTS
In the present work calculations of conformational minima energies were performed for a series of three methylenebis-chlorophenols containing 0166-1280/86/$03.50
0 1986 Elsevier Science Publishers B.V.
148
R5
R15
Fig. 1. Atomic numbering of the methylenebischlorophenol
molecule.
patterns of substitution. Figure 1 shows the adopted notation and Fig. 2 shows the molecular structure of the three compounds. Table 1 gives calculated and experimental values for the dihedral angle 0 between the two aromatic rings, eA and eB respectively between the benzene ring (A or B) and the plane containing CAY- C(H,) bonds, that, is, CZ-CZ1 and Cl* -CZ1, and the torsion angles (7 and 7’) around these bonds. different
DISCUSSION
In ternal angle deformations When H atoms in a benzene molecule are replaced by various atoms or functional groups, changes may result in the electron-withdrawing or releasing properties of the ring and this substitution is known to induce distortions (bond length variations and angular deformations) of the C hexagon from the perfect D 6h symmetry. Angular deformations are the most suitable parameters for the quantitative assessment, of the effect of the different substituents on the geometry of the ring [4]. The crystallographic data are reported in Table 2, and Table 3 gives the angle values obtained by X-ray analysis and FF calculations. It is worth noting here that the internal ring angle of the C carrying the hydroxyl and the chlorine atom is always greater than the ideal value of 120”; on the other hand, it is less than 120” for the C bearing the alkyl group as determined by X-ray analysis [l], which is also supported by calculations.
149
BIFCMT A RX
BIPCNT RX
BIPCNT
13.2 KCAL
BIFCTV 17.1 KCAL
Fig. 2. (a) Compound
WCMT
B RX
BIFCNT 15.5 KCAL
BIPCTV
17 7 KCAL
Ia: BIPCNT;
(b) compound lb
: BIPCMT; (c) compound
1~:
BIWTV.
131-O(5) -67.7(6) 84.4 129 65.3
122.8 133.7 80.6 58 46
122.8 -65 85.8 58 65
-119(2) 75(2) 100 119 76
mol. Q
[13.21a
[15.5]
Exper.c
Theor. mol. p -115(2) 75(2) 102 116 73
BIF’CMT (Ib)
-140 60.6 80 40 61.7
l-121
Theor.
-140 240 81 40 61.4
1151 -100.7(4) 76.9(4) 107.1 100.3 77.7
Exper.d
BIPCW
(Ic)
-103.5 -108 104.5 77.4 72.8
[17.1]
Theor.
-103.5 72 104.4 77.4 72.9
[17.7]
aThe bracketed number is the minimum energy in kcal mol -I . bRef. la. ‘Ref. lb. %f. lc. QTorsion angle C, Cl C,, Cl,, . ?I’orsion angle C,,C, C,,C,. aDihedral angle between planes A and B. hDihedraI angle between planes (C, C,, C,, ) and A. IDihedral angle between planes (C, C,, C,, ) and B.
P ?‘f es s.? @$
Exper.b
BIPCNT (Ia)
Minimum energies and experimental conformations
TABLE 1
151 TABLE 2 Crystallographic data
Space group a (esd) (A) S(A) c(A) 01(deg.) P (deg.) 7 (deg.) z
BIPCNT (Ia) Monoclinic’
BIPCMT (Ib) Crthorhombicb
BIPCTV (Ic) MonoclinicC
P2,lc
p21212,
P2, In
11.977(2) 19.035(3) 9.244(4) 90 109.25( 2) 90 4
3.972(l) 17.593(2) 90 90 90 6 (two molecules (Y and fl in asymmetric unit). 0.057
0.056
R (usual)
12.915(4) 9.157(4) 17.566(3) 90 105.22(3) 90 4
25.284(3)
0.043
aRef. la. bRef. lb. CRef. lc. TABLE 3 Internal benzene ring angles at the carbon atoms bonded to the substituents and central bond angle Substituents
BIPCNT (Ia) Exp .O
BIPCTV (Ic)
BIPCMT (Ib)
Theor.
Ex~.~ Molecule (a)
Molecule (0)
Theor.
Ex~.~
Theor.
OH
123.5(4) 123.9(4)
123.9 123.3
121.9(1.S) 123.3(1.4)
124.1(1.5) 124.1(1.5)
122.4 122.3
122.3(3) 123.1(3)
124.1 123.9
Cl
123.3(S) 121.9(4)
120.9 120.3
124.0(1.6) 125.8(1.5)
125.8(1.6) 123.6(1.5)
1213 121.9
122.7(3) 123.2(3)
121.3 121.2
CH,
117.6(4) 119.3(4)
117.7 113.0
120.9(1.S) 115.8(1.4)
115.6(1.5) 116.6(1.5)
120. 120.
116.4(3) 117.5(3)
119.3 119.3
CH-_(CH, ),
;;;‘$;
115.0 115.3
116.1(1.6) llS.l(l.4)
116.7(1.S) 116.1(1.4)
117.3 117.2
116.3(3) 113.6(3)
117.2 117.4
CH,
117.8(3) 117.0(4)
119.6 119.3
llS.l(l.4) 119.7(1.4)
116.7(1.5) 116.2(1.4)
117.6 117.6
118.4(3) 117.2(3)
117.3 117.3
C*-G-C,,
11&X6(4)
112.1
llS.g(l.3)
116.5(1.4)
113.2
112.1(3)
109.
aRef. la. bRef. lb. cRef. lc.
152
Dihedral angles
They are two minimum energy conformations for each compound: the second one is generated by freezing one phenol ring on this absolute minimum energy and rotating the second phenol ring around its Ch-CH, axis. Free rotations of the benzene rings around C-C,, and C,,-C,, axes are restricted by the ortho substituents: methyl and hydroxyl groups for BIPCNT (Ia) and BIPCMT (Ib), and the hydroxyl group only for BIPCTV (1~). The two conformations obtained are related by an approximate rotation of 180” of the second phenol ring around the Ch-CH2 axis and separated by higher rotational barriers for BIPCNT (280.5 kcal mol-‘) and BIPCMT (529.0 kcal mol-’ ) than for BIPCTV (25.8 kcal mol-’ ). Methylenebisphenols, in the neighbourhood of the calculated minimum energy, also possess a certain rotational freedom.
(a) BIPCNT
1500
(b)
BIPCMT
1000 1000
100 0 :-\.. Om 60,ml~,
B;20z0
360
T’
( c I BIPCTV 50.
IO_ : 0m60,m140,B~20~O0 r’
Fig. 3. Energy of the molecule: E = f (7’).
360
153
The dihedral angles between the two rings A and B are the same in the crystal state and the isolated molecule for the three compounds. The experimental and calculated conformations show a slight discrepancy for 0~ or 6s dihedral angles. Compounds Ia and Ic adopt, approximately, the second minimum energy. Intramolecular OH 0 hydrogen bonds (compounds Ia: 3.05 A. [la] ; Ib; 2.76 W and 2.71 A [lb] ; and Ic: 2.82 A [lc]) may control the conformation in the solid state. The molecules are all helical with 0~ or for experimental and = 40-80” for calculated conformations. OB = 50-80” In the crystal structure the valence angle C-C-C at the bridging group, Czl, is always different from the tetrahedral value and varies widely in the range 112-120”: BIPCNT 118.6” [4], BIPCMT 116” [l], and BIPCTV 112.1” [3]. The Calculation yields values of: BIPCNT 112.1”, BIPCMT 113.2”, and BIPCTV 109”. At the minimum energy level, the valence angle C-C-C at Co1 can be increased to the value found in the crystal structure by increasing the energy by ca. 0.8 kcal mol-’ (BIPCNT), 0.3 kcal mol-’ (BIPCMT), and 0.1 kcal mol-’ (BIPCTV). l
l
l
CONCLUSION
Since the energy barriers separating the two energy minima (Fig. 3) are high, conformational energy calculations indicate that two conformers could possibly be relevant to drug-receptor interactions. Of course knowledge of the interactions of drug molecules with the receptor is crucial in the understanding of the pharmacological features of this series of compounds. It should be emphasized that this analysis examines only the intrinsic conformational tendencies and the number of conformers of the molecule and yields nothing more than an inventory of possible or impossible conformations (or configurations). REFERENCES 1
(a) S. Rantsordas, M. Perrin and A. Thozet, Acta Crystaiiogr., Sect. B, 34 (1978) 1198. (b) S. Rantsordas, M. Perrin, A. Thozet and S. Lecocq, Acta Crystallogr., Sect. B, 37 (1981) 1253. (c)S. Rantsordas and M. Perrin, Acta Crystahogr., Sect. B, 38 (1982) 1871. (d) F. Nowshad and Mazhar-ul-Haque, J. Chem. Sot. Perkin Trans. 2: (1976) 623. (e) D. G. Hay and M. F. Mackay, Acta Crystallogr., Sect. B, 35 (1979) 2952. D. G. Hay, P. de Munk and M. F. Mackay, Au&. J. C&em., 33 (1980) 77, 34 (1981) 559. 2 (a) S. R. Byrn, C. W. Graber, and S. L. Midland, J. Org. Chem., 41 (1976) 2283. (b) J. Eckhardt and J. Bernstein, J. Am. Chem. Sot., 94 (1972) 3247. (c)R. M. Tel and J. B. F. N. Engberts, J. Chem. Sot., Perkin Trans. 2: (1976) 483. (d) J. Caillet, P. Claverie, and B. Pullman, Acta Crystallogr., Sect. B, 32 (1976) 2740. 3 (a) F. H. Westheimer, in M. A. Newman (Ed.), Steric Effects in Organic Chemistry, Wiley, New York, 1956, Chap. 12. (b) J. E. Williams, P. J. Stang and P. Von R. Schleyer, Ann. .Rev. Phys. Chem. 19 (1968) 531. (c) In this work we have used the MM, method: N. L. Allinger, J. Am. Chem. Sot., 99 (1977) 8127. 4 (a) A. Domenicano and P. Murray-Rust, Tetrahedron Lett., 24 (1979) 2283. (b) R. Norrestan and L. Schepper, Acta Chem. Stand. Ser. A, 35 (1981) 91.