The molecular conformations of a-D-1-amino-1-Deoxyglucopyranose

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The exocyclic hydroxymethyl group of the -D-1-amino-1-deoxyglucopyranose can rotate around the carbon-carbon bond. Potential energy surface for this rotation has been investigated using ab initio quantum chemical methods. Relevant stationary points, including for the first time rotational transition states have been characterized by full geometry optimization using basis sets 6-31G(d) and 6-31G(2d,lp). There is a total of six stationary points along the hydroxymethyl rotational surface, including three minima and three transition states were identified. The effects of basis set augmentation and electron correlation on the relative energies are small; the relative energies for each stationary point vary by less than 2.5 kJ/mol for all levels of theory considered. The final barriers to hydroxymethyl rotation ranged from 15 to 41 kJ/mol.

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Nội dung Text: The molecular conformations of a-D-1-amino-1-Deoxyglucopyranose

Journal of Chemistry, Vol. 42 (3), P. 388 - 391, 2004 THE MOLECULAR CONFORMATIONS OF -D-1-AMINO-1- DEOXYGLUCOPYRANOSE Received 27-9-2003 Nguyen Dinh Thanh Faculty of Chemistry, University of Natural Sciences, Hanoi National University SUMMARY The exocyclic hydroxymethyl group of the -D-1-amino-1-deoxyglucopyranose can rotate around the carbon-carbon bond. Potential energy surface for this rotation has been investigated using ab initio quantum chemical methods. Relevant stationary points, including for the first time rotational transition states have been characterized by full geometry optimization using basis sets 6-31G(d) and 6-31G(2d,lp). There is a total of six stationary points along the hydroxymethyl rotational surface, including three minima and three transition states were identified. The effects of basis set augmentation and electron correlation on the relative energies are small; the relative energies for each stationary point vary by less than 2.5 kJ/mol for all levels of theory considered. The final barriers to hydroxymethyl rotation ranged from 15 to 41 kJ/mol. I - Introduction this work reports ab initio quantum chemical calculations on various rotation conformers of Some compounds containing -D-glucosyl- -D-1-amino-1-deoxyglucopyranose (figure l) amine (i.e. -D-1-amino-1-deoxygluco- to characterize quantitatively the complete pyranose) were found in the nature. For intrinsic gas-phase exocyclic hydroxymethyl example, the glucosylamines of procainamide rotational surface. and the pharmacokinetics of the beta- glucosylamine of procainamide in the conscious II - Computational Model rabbit were evaluated [1]. It is similar in -D-2- amino-2-deoxyglucopyranose, a particularly Structure, relative energies, and vibrational critical region of the glucopyranose conforma- frequencies of the particular stationary points, tional surface relates to rotation of the exocyclic including stable minima and the transition hydroxymethyl group [3, 4]. Three minimum states connecting them, associated with rotation conformations were found along the exocyclic about the exocyclic C5-C6 bond have been hydroxymethyl rotational surface designated determined at the restricted Hartree-Fock GG (gauche gauche), GT (gauche trans), and (RHF) at the correlated levels using basic sets TG (trans gauche), each separated by ranging in quality from 6-31G(d) and 6- approximately 120o dihedral rotation. The 31G(2d,1p). Effects of dynamical electron relative energy differences between conformers correlation on the molecular structure and the of was small (< 4 kJ/mol) and somewhat basic relative energies were estimated using second- set dependent [5]. order MØller-Plesset perturbation theory (MP2) Continuing the previous articles about - at level 6-31G(d) [6] and the density-functional and -2-amino-2-deoxyglucopyranoses [3, 4], methods (DFT), employing the Becker’s three 388 parameter hybrid exchange functionals [7 - 9]. levels. The rotational surface consists of three The most stable overall rotational stable minima. Starting from the most stable conformation of the -D-1-amino-1- rotational conformer at the RHF 6-31G(d) level, deoxygluco-pyranose, in which the hydroxyl TG, in which the hydroxymethyl group is groups at C1 through C4 are in a approximately parallel to the ring with a O5-C5- counterclockwise arrangement, was chosen as C6-O6 dihedral angle ( ) of 167.83o, rotation the reference state (figure 1), consistent with about leads initially to transition structure TS1 Polavarapu and Ewig [10] and Glennon et al ( = -130.33o), and then to a second minimum [5]. All calculations were performed using structure GG ( = -56.50o), in which the GAMESS 6.2 electronic structure package [11]. hydroxymethyl group is roughly perpendicular to the glucopyranose ring. Continued rotation O6 O6 about leads to a second transition state, TS2 ( C6 O4 C6 = 0.94o), followed by a third minimum, GT ( = C4 C5 O4 59.40o). Further rotation about leads back to O5 C4 C5 O3 O5 the initial structure TG through a third C3 C2 O3 C3 transition state, TS3 ( = 59.29o). Aside from C1 C2 C1 slight variation in the C5-C6 bond distance O2 N1 N1 between each minimum and their associated O2 rotational transition states due to electron- a b electron repulsion, the overall structures of the various rotational conformers are very similar, Figure 1. TG conformation of -D-1-amino-1- with the orientation of the primary hydroxyl deoxyglucopyranose with appropriate atom group as only exception. labels: (a) counterclockwise and (b) clockwise. Bond distances are those obtained at the RHF 6- The conformational energy surfaces of 31G(d) and MP2 6-31 G(d) levels of theory hexoses, in general, and of glucopyranose, in particular, are extremely complex. Given the III - Results and Discussion rotational freedom of the hydroxyl groups, there are thousands of possible conformers. However, A three-dimensional representation of the the complexity can be greatly reduced when most stable conformer of -D-1-amino-1- intramolecular hydrogen bonding is considered deoxyglucopyranose are shown in figure 1 in in preliminary conformation search, i.e., the low the counterclockwise arrangement, designated lying conformation should maximize TG (trans gauche) along with important bond intramolecular hydrogen bonding. For the distances obtained at the RHF 6-31G(d) and 6- isolated molecule, the hydroxyls prefer to orient 31G(2d,1p) levels. Basis set expansion through in such a way as to yield a cooperative 6-31G(2p,1d) was found to only moderately hydrogen bonding that is as efficient as affect these structural parameters. For the C-C, possible. For glucopyranose, the OH groups C-O, O-H and N-H bonds, basis set expansion may take clockwise (figure 1a) or causes a contraction (ca. 0.0008 - 0.0068 Å) counterclockwise (figure 1b) orientations. It was found previously that the counterclockwise while the C-H bonds are elongated (ca. 0.0007 - orientation was preferred, and that preference 0.0013 Å); especially, the C-N bond is was confirmed in this work. For a TG elongated a little. The reason for this is not glucopyranose, the counterclockwise clear; it could be a result of the limited conformation was found to be -9.41 kJ/mol flexibility of the 6-31G(d) basis set. more stable than the corresponding clockwise Figure 2 shows a graphical representation of conformation at the RHF 6-31G(d) level the hydroxymethyl rotational energy surface at (Absolute energies of the TG counterclockwise both the RHF 6-31G(d) and 6-31G(2d,1p) and clockwise conformations are -663.496975 389 and -663.500558 hartrees, respectively). TS1 Figure 2: Relative energy 40.76 diagram (kJ/mol) at the RHF 6- 31G(d) (solid line) and 6- 38.44 31G(2d,1p) (dashed line) levels of TS2 25.79 theory for the stationary points TS3 along the exocyclic hydroxy- 25.37 16.53 methyl rotational surface of -D- 14.23 1-amino-1-deoxyglucopy-ranose. GT The internal coordinate is TG GG TG 0.22 0.0 defined as the O6-C6-C5-O5 0.0 -1.12 -0.29 dihedral angle -1.46 Table 1: Relative energy, E, for conformations Tables 1 and 2 list the relative energetic of -D-1-amino-1-deoxygluco-pyranose data for each stationary point on the rotational (kJ/mol) surface at various ab initio computational levels. The relative energetic data for each Level of Theory stationary point are only modest influenced by Confor. a RHF basis set augmentation over the RHF 6-31G(d), RHF MP2 6-31G 6-31G(2d,1p), with shifts of less 3 kJ/mol 6-31G(d) 6-31G(d) (2d,1p) overall. Three minimum conformations (TG, TG GG, GT) are found to be different in energy. 0.0 b 0.0b 0.0 (167.59o) The TG conformation is the most stable, and the TS1 relative energy differences between two remain 40.76 38.44 (-130.59o) minimum conformers (GG and GT) are 1.33 GG -1.12 -1.46 -1.74 and 1.17 kJ/mol at the RHF 6-31G(d) and RHF (-56.96o) 6-31G(2d,1p), respectively. Thus, the TG TS2 25.79 25.37 conformer is, maybe, the more stable one in the (1.05o) gas phase. The relative final ordering, obtained GT 0.22 -0.29 1.40 at the RHF 6 31G(d) for free energies (in (60.33o) TS3 kJ/mol), is GG (-0.103) > GT (-0.037) > TG 16.53 14.23 (0.0). (60.00o) a Values in parentheses are the O5-C5-C6-O6 All the stationary points identified on the dihedral angles of the RHF 6-31G(2d,1p) optimized hydroxymethyl rotational surface consist of geometries. bAbsolute energies for the TG conformations that are influenced by conformation, in hartrees, are -663.496975, - intramolecular interactions between the C6 663.563862 and -665.3305994 for RHF 6-31G(d), hydroxyl and nearby oxygens (A hydrogen RHF 6-31G(2d,1p) and MP2 6-31G(d) calculations, respectively. The TG conformer was defined as zero bond is defined by an O-H distance of less 2.6 by convention. Å and an O-H-O angle of greater than 120o, 390 Table 2: Corrected Energies for hydrogen-bonding threshold and the stability of conformations of -D-1-amino-1-deoxygluco- the conformers, suggesting that the somewhat pyranose (kJ/mol) arbitrary definition of hydrogen bonding loses its meaning when referring to intramolecular Conforme (E+ZPVE) r a H og b G og b interactions in carbohydrates. The amino-group on C1 atom also forms an TG 0.00 0.00 0.00 intramolecular hydrogen bond with the oxygen TS1 5.71 7.46 9.69 atom O5. The values of N1H-O5 distances and N1-N1H-O5 angles for the conformation are GG 0.76 0.57 -0.103 following: GG 2.3948 Å, 103.82o; GT 2.4005 TS2 4.44 6.20 8.13 Å, 104.04o; TG 2.3990 Å, 103.95o; TS1 2.4070 GT 1.24 0.91 -0.037 Å, 104.18; TS2 2.3877 Å , 104.81o; TS3 2.3838 TS3 6.83 8.27 8.07 Å, 105.28o. Interestingly, the intramolecular a hydrogen bond in all conformers has the same Zero-point vibrational energy (ZPVE) stability. The intrinsic exocyclic hydroxymethyl corrections were calculated from harmonic vibrational frequencies determined at the RHF 6- rotational barriers in glucopyranose are 31G(d) level and scaled by a factor of 1.00 in accord substantial, ranging from ~34 kJ/mol for TS1 to ~20 kJ/mol for TS2, depending on the level of with known overestimates at this level. b H og theory. Similar to the minima, the basis set = (E + ZPVE) + CpT and G og = H og augmentation has affected on the structures or the relative energies of the rotational transition T. Sog are the relative gas-phase enthalpy and free states. Moreover, based on the final ab initio energy, respectively. results, the relative transition state energies are in order TS3 > TS2 > TS1, indicating that the consistent with the definition of Glennon et al most facile interconversion in the gas phase is [7]). In the TG conformer, the C6 hydroxyl between TG and GT. forms an intramolecular hydrogen bond with O4 (O6H-O4 distance 2.1088 Å, O6-O6H-O4 III - Conclusion angle 133.54o), and in the TS1 transition state, this hydrogen bond is not maintained (O6H-O4 The rotational energy surface for the distance 3.0186 Å, O6-O6H-O4 angle 74.74o). exocyclic hydroxymethyl group of -D-1- In the GG conformer, O6H does not form a amino-1-deoxyglucopyranose has been hydrogen bond with O4 (O6H-O4 distance described using high-level ab initio methods. 4.1700 Å, O6-O6H-O4 angle 50.62o), and These data definitively establish the potential instead of orienting toward O4, O6H orients energy surface along this coordinate in the gas toward O5 in this conformer and form a phase. hydrogen bond with O5 formed (O6H-O5 distance 2.3341 Å, O6-O6H-O5 angle 105.00o), This publication was financially supported but it is not a true hydrogen bond. In the TS2 by the National Basic Research Program in transition state O6H does form a hydrogen bond Natural Sciences. with O5 (O6H-O5 distance 1.9496 Å, O6-O6H- O5 angle 119.98o). But the GT conformer, O6H References does not form a true hydrogen bond with O5 although still oriented toward O5 (O6H-O5 1. J. E. Parkin, K. F. Ilett, European Journal distance 2.3341 Å, O6-O6H-O5 angle 106.06o). of Pharmaceutics and Biopharmaceutics, 43, P. 139 - 143 (1997). There is no apparent relation between those interaction that are within the specific (Continued page 383) 391 M. A. Fabian, J. Brunckova, B. K. Ohta. J. Am. 6. A. D. Becker. Phys. Rev., A38, 3098 Chem. Soc., 121, 6911 (1999). (1988). 2. Nguyen Dinh Thanh, Dang Nhu Tai. 7. A. D. Becker. J. Chem. Phys., 98, 5648 Journal of Chemistry (2003) (in press). (1993). 3. Nguyen Dinh Thanh, Dang Nhu Tai. 8. C. Lee, W.Yang and R. G. Parr. Phys. Journal of Chemistry, VNU (2003) (in Rev., B37, 785 (1988). press). 9. P. L. Polavaru, C. S. Ewig J. 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