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Conformational analysis of phenylsulphonylalkanoic acids with the AM1 method
Journal of Molecular Structure (Theochem), 283 (1993) 207-211 0166-1280/93/%06.00 0 1993 - Elsevier Science Publishers B.V. All rights reserved
207
Conformational analysis of phenylsulphonylalkanoic acids with the AM1 method Maria Jaworska, Jarosaw Polaliski, Aleksander Ratajczak* Institute of Chemistry, Silesian University, 9 Szkolna Street, PI-40006 Katowice, Poland (Received 19 March 1992) Abstract AM1 molecular orbital calculations were carried out for a series of compounds having the formula Ph-SO*--CR’R’-COOH, some of which possess a sweet taste. The minimum-energy conformation with an intramolecular hydrogen bond was found for each compound investigated.
Introduction
The class of compounds having the general formula Ph-S02-CR’R2COOH, where R’ and R2 are alkyl or cycloalkyl groups, is characterized by a sweet taste [l]. The intensity and quality of their taste depend strongly on the R’ and R2 groups; however, the structure-taste interdependence can be neither easily formulated nor understood [1,2]. According to Shallenberger - theory of sweet taste [3], a polarized group A-H and an electronegative atom B in an active molecule form hydrogen bonds with an electronegative group and an electropositive hydrogen atom in the receptor respectively. Kier [4] augmented this model by assuming the existence of a hydrophobic site in a sweet molecule at a distance of approximately 3.6 A from A-H. The difference in sweetness is an indirect effect of the conformational difference between sweet and unsweet molecules. Hence, we thought it of interest to determine and to better understand the relationship between the lowest-energy conformers and sweetness. Such an approach has proved success* Corresponding
author.
ful in many QSAR studies of the structure-taste problem [5]. Other methods, like comparing the molecular electrostatic potential (MEP) maps of sweet molecules, have also given good results in elucidating the sweetness of molecules [6,7]. In the present study a conformational analysis of compounds l-8 (Table 1) was carried out by means of the AM 1 method [8]. During the calculations, all the structural parameters were optimized. Results and discussion
Lee [9] introduced the idea that the conformation of sweet molecules is stabilized by a hydrogen bond. This bond may “prepare” the molecule for a proper interaction with a receptor. For example, intramolecular hydrogen bonding has been reported to be one of the main factors determining the sweetness of sugars [lo]. Intermolecular hydrogen-bonded structures are very common among carboxylic acids and their derivatives. Moreover, intramolecular hydrogen-bonded structures have been observed and reported among some a-alkoxy [11,12], o-sulphonylacetic acids [13] and P-sulphinylenamines [14]. The results of the present AM1 calculations on
208
M. Jaworska et al./J. Mol. Struct. (Theo&em) 283 (1993) 207-211
Table 1 Compounds l-8 and their relative saccharose RS = 1)
sweetness
(RS) (for
Table 2 Some optimized dihedral angles for l-8 Compound
PhSO 2 CR’R’COOH
R’
R2
RSa
H H H H H
H Me Et i-Pr Pr
Et Me
Et i-Pr
0 0 11 110 0 110 0 44
Dihedral angle (deg) 11-9-1-2
4-3-2-l
8-4-3-2
3-2-l-9
90 -82 -78 -69 -80 -72 -80 -68
55 54 58 66 59 67 56 63
-6 -2 -3 -11 -4 -11 1 -7
72 65 62 70 62 73 62 60
a From Ref. 1 and 2.
compounds l-8 indicate that an intramolecular hydrogen bond may also play a role in the sweetness of phenylsulphonylalkanoic acids. Figures 1 and 2 show the lowest-energy conformations
Fig. 1. The lowest-energy
found by calculations on the investigated compounds, along with the atom numbering. Some optimized dihedral angles are given in Table 2. Comparison of these angles shows that all the
conformations
for compounds
1-4.
M. Jaworska et al./J. Mol. Struct. (Theochem) 283 (1993) 207-211
Fig. 2. The lowest-energy
209
conformations
molecules investigated adopt a similar conformation. In all cases a six-membered ring 06-Sl -C2-C3-04-H8 in which the carboxyl hydrogen atom (H8) is bonded to the oxygen atom (06) of the sulphonyl group is formed. This hydrogen-bonded- six-membered ring is folded, as can be seen from Table 2 and Figs. 1 and 2. Some calculated interatomic distances are given in Table 3. The distance H8-06 varies from 2.11 to 2.22A for compounds 1-8. The sweetness of the investigated compounds, relative to that of saccharose (RS), is given in Table 1. Compounds 3, 4,6 and 8 are sweet, the others are unsweet. Inspection of Table 3 shows that all the 04-06 distances fall in the region predicted by Shallenberger’s theory of the A-B distance, which is 2.5-4A.
for compounds
5-8.
The role of the hydrophobic centre may be played by atom Cl0 or Cl2 the distances of which from 04 are comparable with the distance of 3.6A postulated by Kier [4]. While the C4-Cl0 distances in all the compounds investigated falls within the Kier postulated value of 3.6A, compound 1 in which the atom Cl2 is not present, compound 2 in which the 04-Cl2 distance is shorter and the fact that neither 1 or 2 is sweet could indicate that the alkyl R2 group is the hydrophobic centre. However, as a hydrophobic centre should be not seen as always necessary, but rather as required for the optimum receptor stimulation [lo], such a conclusion can only be suggested tentatively. Figures 3 and 4 show superimpositions of the conformations of the sweet and unsweet com-
210
M. Jaworska et al/J. Mol. Struct. (Theochem)
283 (1993) 207-211
Table 3 Some interatomic distances (A) in the lowest-energy conformations of l-8 Bond
H8-06 04-06 04-Cl2 04-Cl0 04-Cl1 04-c9 04-Cl3 04-Cl4
Compound 1
2
3
4
5
6
7
8
2.16 2.87
2.22 2.92 2.68 3.55 5.07 3.80
2.15 2.85 3.76 3.50 5.09 3.78 4.32 5.09
2.15 2.77 3.74
2.14 2.84 3.77 3.53 5.10 3.80 4.55
2.17 2.78 3.73 3.89 5.34 4.04 4.10 5.03
2.11 2.79 3.75 3.44 5.04 3.75
2.12 2.76 3.76 3.58 5.25 3.89 4.21 5.03
3.87 5.16 3.95
pounds respectively. It is probable that an extended aliphatic group at R1 and R2, as in 5 and 7, may be one of the factors influencing sweet potency, in this case inhibiting the interaction between molecule and receptor. The results of the AM1 calculations show that
arylsulphonylalkanoic acids differ from the similar glucophores in the mode of action of the carboxyl group. Usually it is the carboxyl group that accepts a hydrogen atom from the receptor in anionic COO- [IS] (for example, cr-amino acids NH;/ COO-). In the compounds studied in this paper the carboxyl group (COOH) provides the hydrogen atom for the operation in the Shallenberger
Fig. 3. Superimpositions of the conformations of the sweet molecules 3,4, 6 and 8.
5.36 4.01 4.09 4.98
5.02
AH-B theory. Sodium salts of the active acids are sweet, while esterification (the ethyl ester of the acid 4; Table 4) quenches sweetness [l]. This behaviour resembles that of saccharin, in which substitution of the imide hydrogen atom results in the disappearance of taste, while the alkali metal salts are active [ 161.Such salts at least formally lack the carboxylic or imide hydrogen atom, and an explanation of their activity must be offered which remains in agreement with the Shallenberger model. It seems quite likely that the hydrogen atom in this case originates from water, which in the natural environment of the receptor always
Fig. 4. Superimpositions of the conformations of the unsweet molecules 1, 2,5 and 7.
M. Jaworska et al./J. Mol. Struct.
(Theochem)
211
283 (1993) 207-211
solubilizes glucophores. Another possibililty is that, although taste can be attributed to the presence of a COOH/S02 or NH/SO2 moiety, the alternative Shallenberger entity could involve the benzene ortho-hydrogen atom and SO2, as has been suggested for analogous nitro compounds [31. The uncommon behaviour of structures having a similar carboxyl group seems to be worthy of mention. It has been reported that alkoxyalkanoic acids are potent sweet inhibitors, i.e. they prevent glucophore-receptor interactions. The actual mechanism of this inhibition has not been explained, but the preferential inhibitor-receptor or inhibitor-glucophore interaction has been suggested as the probable explanation [17].
References 1 A. Ratajczak 2
3 4 5
6 I 8
Conclusions
9
The preferential conformations of arylsulphonylalkanoic acids calculated by means of the AM1 method show that the class can be fitted into the Shallenberger and Kiergeometry requirements. Although the method does not provide a full explanation, it shows that intramolecular hydrogen bonding effects do not differentiate these compounds into active and inactive ones. Thus it is the alkyl groups that seem to have the decisive influence on the sweetness of the investigated compounds.
10
Acknowledgement
16 17
The authors are indebted to Professor Henryk Ratajczak of the Wroclaw University for his critical comments on this paper.
11 12 13 14 15
and J. Polariski, Naturwissenschaften, 78 (1991) 69. J. Polar’& and A. Ratajczak, Structure-Taste Study of a New Class of Artificial Sweeteners, Arylsulfonylalkanoic Acids, Mini ECRO Symposium, Reims, France, 1991 in M. Matlouthi, J.A. Kanters, and G.G. Birch (Eds.), Sweet Taste Chemoreception, Elsevier, Barking, 1993, pp. 185-203. R.S. Shallenberger and T.E. Acree, Nature, 216 (1967) 480. L.B. Kier, J. Pharm. Sci., 61 (1972) 1394. E. Benedetti, B. Di Blasio, V. Pavone, C. Pedone, W.D. Fuller, D.F. Mierke and M. Goodman, J. Am. Chem. Sot., 112 (1990) 8909. T.J. Venanzi and C.A. Venanzi, J. Med. Chem., 31 (1988) 1879. T.J. Venanzi and C.A. Venanzi, Anal. Chim. Acta, 21 (1988) 213. M.J.S. Dewar, E.G. Zoebisch, E.F. Healy and J.J.P. Stewart, J. Am. Chem. Sot., 107 (1985) 3902. C.K. Lee, Adv. Carbohydr. Chem. Biochem., 45 (1987) 199. R.S. Shallenberger and G.G. Birch, Sugar Chemistry, AVI, Westport, CT, 1975, pp. 117-118. M. Oki and M. Hirota, Bull. J. Chem. Sot., 34 (1960) 374. M. Oki and M. Hirota, Bull. J. Chem. Sot., 33 (1960) 119. D.J. Pasto and R. Kent, J. Org. Chem., 30 (1965) 2684. L. Kozerski and R. Kawqcki, Phosphorus Sulfur Silicon, 59 (1991) 201. J.M. Tinti and C. Nofre, Design of sweeteners: a rational approach, in D.E. Walters, F.T. Orthoefer and G.E. Dubois (E&X.), Sweeteners: Discovery, Molecular Design and Chemoreception, ACS Symp. Ser. 450, American Chemical Society, Washington, DC, 1991, p. 88. G.H. Hamor, Science, 134 (1961) 1416. M.G. Lindley, Phenoxyalkanoic Acid Sweetness Inhibitors, in D.E. Walters, F.T. Orthoefer and G.E. Dubois (Eds.), Sweeteners: Discovery, Molecular Design and Chemoreception, ACS Symp. Ser. 450, American Chemical Society, Washington, DC, 1991, p. 251.
207
Conformational analysis of phenylsulphonylalkanoic acids with the AM1 method Maria Jaworska, Jarosaw Polaliski, Aleksander Ratajczak* Institute of Chemistry, Silesian University, 9 Szkolna Street, PI-40006 Katowice, Poland (Received 19 March 1992) Abstract AM1 molecular orbital calculations were carried out for a series of compounds having the formula Ph-SO*--CR’R’-COOH, some of which possess a sweet taste. The minimum-energy conformation with an intramolecular hydrogen bond was found for each compound investigated.
Introduction
The class of compounds having the general formula Ph-S02-CR’R2COOH, where R’ and R2 are alkyl or cycloalkyl groups, is characterized by a sweet taste [l]. The intensity and quality of their taste depend strongly on the R’ and R2 groups; however, the structure-taste interdependence can be neither easily formulated nor understood [1,2]. According to Shallenberger - theory of sweet taste [3], a polarized group A-H and an electronegative atom B in an active molecule form hydrogen bonds with an electronegative group and an electropositive hydrogen atom in the receptor respectively. Kier [4] augmented this model by assuming the existence of a hydrophobic site in a sweet molecule at a distance of approximately 3.6 A from A-H. The difference in sweetness is an indirect effect of the conformational difference between sweet and unsweet molecules. Hence, we thought it of interest to determine and to better understand the relationship between the lowest-energy conformers and sweetness. Such an approach has proved success* Corresponding
author.
ful in many QSAR studies of the structure-taste problem [5]. Other methods, like comparing the molecular electrostatic potential (MEP) maps of sweet molecules, have also given good results in elucidating the sweetness of molecules [6,7]. In the present study a conformational analysis of compounds l-8 (Table 1) was carried out by means of the AM 1 method [8]. During the calculations, all the structural parameters were optimized. Results and discussion
Lee [9] introduced the idea that the conformation of sweet molecules is stabilized by a hydrogen bond. This bond may “prepare” the molecule for a proper interaction with a receptor. For example, intramolecular hydrogen bonding has been reported to be one of the main factors determining the sweetness of sugars [lo]. Intermolecular hydrogen-bonded structures are very common among carboxylic acids and their derivatives. Moreover, intramolecular hydrogen-bonded structures have been observed and reported among some a-alkoxy [11,12], o-sulphonylacetic acids [13] and P-sulphinylenamines [14]. The results of the present AM1 calculations on
208
M. Jaworska et al./J. Mol. Struct. (Theo&em) 283 (1993) 207-211
Table 1 Compounds l-8 and their relative saccharose RS = 1)
sweetness
(RS) (for
Table 2 Some optimized dihedral angles for l-8 Compound
PhSO 2 CR’R’COOH
R’
R2
RSa
H H H H H
H Me Et i-Pr Pr
Et Me
Et i-Pr
0 0 11 110 0 110 0 44
Dihedral angle (deg) 11-9-1-2
4-3-2-l
8-4-3-2
3-2-l-9
90 -82 -78 -69 -80 -72 -80 -68
55 54 58 66 59 67 56 63
-6 -2 -3 -11 -4 -11 1 -7
72 65 62 70 62 73 62 60
a From Ref. 1 and 2.
compounds l-8 indicate that an intramolecular hydrogen bond may also play a role in the sweetness of phenylsulphonylalkanoic acids. Figures 1 and 2 show the lowest-energy conformations
Fig. 1. The lowest-energy
found by calculations on the investigated compounds, along with the atom numbering. Some optimized dihedral angles are given in Table 2. Comparison of these angles shows that all the
conformations
for compounds
1-4.
M. Jaworska et al./J. Mol. Struct. (Theochem) 283 (1993) 207-211
Fig. 2. The lowest-energy
209
conformations
molecules investigated adopt a similar conformation. In all cases a six-membered ring 06-Sl -C2-C3-04-H8 in which the carboxyl hydrogen atom (H8) is bonded to the oxygen atom (06) of the sulphonyl group is formed. This hydrogen-bonded- six-membered ring is folded, as can be seen from Table 2 and Figs. 1 and 2. Some calculated interatomic distances are given in Table 3. The distance H8-06 varies from 2.11 to 2.22A for compounds 1-8. The sweetness of the investigated compounds, relative to that of saccharose (RS), is given in Table 1. Compounds 3, 4,6 and 8 are sweet, the others are unsweet. Inspection of Table 3 shows that all the 04-06 distances fall in the region predicted by Shallenberger’s theory of the A-B distance, which is 2.5-4A.
for compounds
5-8.
The role of the hydrophobic centre may be played by atom Cl0 or Cl2 the distances of which from 04 are comparable with the distance of 3.6A postulated by Kier [4]. While the C4-Cl0 distances in all the compounds investigated falls within the Kier postulated value of 3.6A, compound 1 in which the atom Cl2 is not present, compound 2 in which the 04-Cl2 distance is shorter and the fact that neither 1 or 2 is sweet could indicate that the alkyl R2 group is the hydrophobic centre. However, as a hydrophobic centre should be not seen as always necessary, but rather as required for the optimum receptor stimulation [lo], such a conclusion can only be suggested tentatively. Figures 3 and 4 show superimpositions of the conformations of the sweet and unsweet com-
210
M. Jaworska et al/J. Mol. Struct. (Theochem)
283 (1993) 207-211
Table 3 Some interatomic distances (A) in the lowest-energy conformations of l-8 Bond
H8-06 04-06 04-Cl2 04-Cl0 04-Cl1 04-c9 04-Cl3 04-Cl4
Compound 1
2
3
4
5
6
7
8
2.16 2.87
2.22 2.92 2.68 3.55 5.07 3.80
2.15 2.85 3.76 3.50 5.09 3.78 4.32 5.09
2.15 2.77 3.74
2.14 2.84 3.77 3.53 5.10 3.80 4.55
2.17 2.78 3.73 3.89 5.34 4.04 4.10 5.03
2.11 2.79 3.75 3.44 5.04 3.75
2.12 2.76 3.76 3.58 5.25 3.89 4.21 5.03
3.87 5.16 3.95
pounds respectively. It is probable that an extended aliphatic group at R1 and R2, as in 5 and 7, may be one of the factors influencing sweet potency, in this case inhibiting the interaction between molecule and receptor. The results of the AM1 calculations show that
arylsulphonylalkanoic acids differ from the similar glucophores in the mode of action of the carboxyl group. Usually it is the carboxyl group that accepts a hydrogen atom from the receptor in anionic COO- [IS] (for example, cr-amino acids NH;/ COO-). In the compounds studied in this paper the carboxyl group (COOH) provides the hydrogen atom for the operation in the Shallenberger
Fig. 3. Superimpositions of the conformations of the sweet molecules 3,4, 6 and 8.
5.36 4.01 4.09 4.98
5.02
AH-B theory. Sodium salts of the active acids are sweet, while esterification (the ethyl ester of the acid 4; Table 4) quenches sweetness [l]. This behaviour resembles that of saccharin, in which substitution of the imide hydrogen atom results in the disappearance of taste, while the alkali metal salts are active [ 161.Such salts at least formally lack the carboxylic or imide hydrogen atom, and an explanation of their activity must be offered which remains in agreement with the Shallenberger model. It seems quite likely that the hydrogen atom in this case originates from water, which in the natural environment of the receptor always
Fig. 4. Superimpositions of the conformations of the unsweet molecules 1, 2,5 and 7.
M. Jaworska et al./J. Mol. Struct.
(Theochem)
211
283 (1993) 207-211
solubilizes glucophores. Another possibililty is that, although taste can be attributed to the presence of a COOH/S02 or NH/SO2 moiety, the alternative Shallenberger entity could involve the benzene ortho-hydrogen atom and SO2, as has been suggested for analogous nitro compounds [31. The uncommon behaviour of structures having a similar carboxyl group seems to be worthy of mention. It has been reported that alkoxyalkanoic acids are potent sweet inhibitors, i.e. they prevent glucophore-receptor interactions. The actual mechanism of this inhibition has not been explained, but the preferential inhibitor-receptor or inhibitor-glucophore interaction has been suggested as the probable explanation [17].
References 1 A. Ratajczak 2
3 4 5
6 I 8
Conclusions
9
The preferential conformations of arylsulphonylalkanoic acids calculated by means of the AM1 method show that the class can be fitted into the Shallenberger and Kiergeometry requirements. Although the method does not provide a full explanation, it shows that intramolecular hydrogen bonding effects do not differentiate these compounds into active and inactive ones. Thus it is the alkyl groups that seem to have the decisive influence on the sweetness of the investigated compounds.
10
Acknowledgement
16 17
The authors are indebted to Professor Henryk Ratajczak of the Wroclaw University for his critical comments on this paper.
11 12 13 14 15
and J. Polariski, Naturwissenschaften, 78 (1991) 69. J. Polar’& and A. Ratajczak, Structure-Taste Study of a New Class of Artificial Sweeteners, Arylsulfonylalkanoic Acids, Mini ECRO Symposium, Reims, France, 1991 in M. Matlouthi, J.A. Kanters, and G.G. Birch (Eds.), Sweet Taste Chemoreception, Elsevier, Barking, 1993, pp. 185-203. R.S. Shallenberger and T.E. Acree, Nature, 216 (1967) 480. L.B. Kier, J. Pharm. Sci., 61 (1972) 1394. E. Benedetti, B. Di Blasio, V. Pavone, C. Pedone, W.D. Fuller, D.F. Mierke and M. Goodman, J. Am. Chem. Sot., 112 (1990) 8909. T.J. Venanzi and C.A. Venanzi, J. Med. Chem., 31 (1988) 1879. T.J. Venanzi and C.A. Venanzi, Anal. Chim. Acta, 21 (1988) 213. M.J.S. Dewar, E.G. Zoebisch, E.F. Healy and J.J.P. Stewart, J. Am. Chem. Sot., 107 (1985) 3902. C.K. Lee, Adv. Carbohydr. Chem. Biochem., 45 (1987) 199. R.S. Shallenberger and G.G. Birch, Sugar Chemistry, AVI, Westport, CT, 1975, pp. 117-118. M. Oki and M. Hirota, Bull. J. Chem. Sot., 34 (1960) 374. M. Oki and M. Hirota, Bull. J. Chem. Sot., 33 (1960) 119. D.J. Pasto and R. Kent, J. Org. Chem., 30 (1965) 2684. L. Kozerski and R. Kawqcki, Phosphorus Sulfur Silicon, 59 (1991) 201. J.M. Tinti and C. Nofre, Design of sweeteners: a rational approach, in D.E. Walters, F.T. Orthoefer and G.E. Dubois (E&X.), Sweeteners: Discovery, Molecular Design and Chemoreception, ACS Symp. Ser. 450, American Chemical Society, Washington, DC, 1991, p. 88. G.H. Hamor, Science, 134 (1961) 1416. M.G. Lindley, Phenoxyalkanoic Acid Sweetness Inhibitors, in D.E. Walters, F.T. Orthoefer and G.E. Dubois (Eds.), Sweeteners: Discovery, Molecular Design and Chemoreception, ACS Symp. Ser. 450, American Chemical Society, Washington, DC, 1991, p. 251.