Comparison between Diketones and Diamides: Effects of Carbonyl

J. Phys. Chem. 1996, 100, 16131-16136

16131

Comparison between Diketones and Diamides: Effects of Carbonyl Groups on the Conformational Preferences of Small Aliphatic Segments Carlos Alema´ n,* Eloı´sa Navarro, and Jordi Puiggalı´* Departament d’Enginyeria Quı´mica, E.T.S. d’Enginyers Industrials de Barcelona, UniVersitat Polite` cnica de Catalunya, Diagonal 647, Barcelona E-08028, Spain ReceiVed: April 30, 1996; In Final Form: August 5, 1996X

The conformational preferences of a set of diketones have been investigated by ab initio quantum mechanical calculations. In addition, SCRF calculations have been performed in order to ascertain the effect of aqueous and CCl4 solvents. Results indicate that diketones with two or three methylene units between the two carbonyl groups present a folding in the central aliphatic segment. More specifically, the central methylene units adopt a gauche conformation. Results have been compared with those previously obtained for related diamides. Finally, the conformational preferences of a compound with only one keto group have been studied. In this case, the lowest energy conformation corresponds to an extended structure, which indicates that the presence of the second carbonyl group plays a crucial role in the folding of methylene units.

Introduction In previous works1-3 we reported an unusual conformational feature found in small diamide compounds using both X-ray crystallography and quantum mechanical calculations. Our studies concluded that central methylene units of aliphatic segments in succinamide (1), glutaramide (2), and adipamide (3) analogues do not keep a trans (T) conformation but tend to fold into a gauche (G) one. Furthermore, the all-trans conformation was not characterized as an energy minimum in 21 in agreement with the results previously found for malonamide derivatives4,5 (4), which also have an odd number of

methylene units. This must be explained in terms of repulsive interactions between the two carbonyl oxygen atoms, which evidently are much stronger in 4 than in 2. These results are very important for organic and macromolecular chemistry, since the methylene segments are usually considered in all-trans conformation in the solid state. For instance, X-ray experiments showed an all-trans conformation for the crystalline part of polyethylene chains.6 More recently, we have extended our experience on the folding of methylene units to the asparagine and glutamine residues7 (5a and 5b, respectively). More specifically, we investigated the conformational preferences of the side chains of 5a and 5b, which have one and two methylene units before the side carbonyl group, respectively. The results indicate that for the sequences C(dO)CHCH2C(dO), C(dO)CHCH2CH2, and CHCH2CH2C(dO) the G conformation is estabilized from an enthalpic point of view. These findings permit rationalization of the relatively frequent G conformations found in peptides * Corresponding authors. X Abstract published in AdVance ACS Abstracts, September 1, 1996.

S0022-3654(96)01245-2 CCC: $12.00

and proteins, which were previously explained in terms of side chain mobility.8 We now wish to extend our studies on the folding of methylene units from diamides to diketones. Wiberg and Martin9 have studied the conformational preferences of some small ketones, i.e. from acetone to butanone, using ab initio quantum mechanical calculations. Their results indicated that SCF-MO calculations with the 6-31G(d) basis set provide reasonable estimations of the experimental data. Furthermore, the effect of electron correlation (estimated at the MP2 and MP3 levels) was found to be very small in these compounds. More recently, Berry et al.10 extended this work to a complete set of ketones, which includes not only open chain compounds but also ketones attached to hydrocarbon rings and cycloalkanones. In this work we investigate the conformational preferences of a set of diketones with a central aliphatic segment. More especifically, computations were performed at the ab initio level on 2,4-pentanedione (6), 2,5-hexanedione (7), and 2,6-heptanedione (8), which contain the same number of central

methylene groups as the previously studied N,N′-dimethylmalonamide (4a), N,N′-dimethylsuccinamide (1a), and N,N′dimethylglutaramide (2a). The effects of the keto and amide groups on the folding of methylene units have been compared along the work. Furthermore, to ascertain the effect of the second keto group in the folding of methylene units a conformational study of 2-hexanone (9) was also performed. The © 1996 American Chemical Society

16132 J. Phys. Chem., Vol. 100, No. 40, 1996

Alema´n et al.

effect of the solvent on the conformational equilibrium was examined by following the self-consistent reaction-field (SCRF) method developed by Miertus, Scrocco, and Tomasi11,12 (MST) and optimized for aqueous13,14 and organic15 solvents by Luque and Orozco. Methods Gas-Phase Calculations. Molecular geometries were optimized at the Hartree-Fock (HF) level of theory using the 6-31G(d)16 basis set. Thus, Wiberg and Martin9 found that the HF/6-31G(d) level chosen for this study should provide reasonable estimates of the conformational energies of ketones. The starting geometries for the conformational search were generated by following the multiconformational analysis, according to which in the compounds under study all the backbone dihedral angles can adopt values around 60°, 180°, and -60°. The nature of all minima was verified by calculating the eigenvalues of the matrix of energy second derivatives (Hessian). Upon conversion to frequencies, the eigenvalues were used to calculate zero-point energies (ZPE) and thermal corrections (TC) at 298 K. The effect of the electron correlation on the relative energies was found to be small in compounds with one keto group. However, some of the compounds investigated here have two keto groups close in the space which would alter this situation. In such cases, single-point calculations were performed at the MP2/6-31G(d) level using the HF/6-31G(d) geometries. MP2 denotes second-order Møller-Plesset perturbation theory.17 Solvent-Phase Calculations. The free energies of solvation (∆Gsolv) were determined using a semiempirical AM1 adapted version of the SCRF developed by Miertus, Scrocco, and Tomasi (MST/AM1). According to this method, the ∆Gsolv was determined as the addition of electrostatic and steric contributions (eq 1). The steric component was computed as the sum

∆Gsolv ) ∆Gelec + ∆Gcav + ∆GvdW

(1)

of the cavitation and van der Waals terms. The cavitation term was determined using Pierotti’s scaled particle theory,18 while the van der Waals term (eq 2) was evaluated by means of a linear relation with the molecular surface area:13-15

∆GvdW ) ∑ξiSi

(2)

i

where Si is the portion of the molecular surface area belonging to atom i and ξi is the hardness of atom i. Parameters defining the hardness of the different atom types in aqueous and CCl4 solvents were determined in previous parametrizations.13,15 The electrostatic interaction between the solute and the solvent was computed using the MST-SCRF approach, in which the solvent is represented as a continuous dielectric, which reacts against the solute charge distribution generating a reaction field. The effect of the solvent reaction field on the solute is introduced as a perturbation operator (VR) in the solute Hamiltonian (eq 3).

(H0 + VR)ψ ) Eψ

(3)

The perturbation operator is computed in terms of a set of point charges located at the solute/solvent interface, i.e. the solute cavity (eq 4).

VR ) ∑qi/|ro - r|

(4)

i

Such imaginary charges were determined by solving the Laplace

Figure 1. Minimum energy conformation of (a) 2,4-pentanedione (6) and (b) N,N′-dimethylmalonamide (4a).

equation at the solute/solvent interface. The electrostatic potential of the solute was computed at the AM1 level using the ortho method.19 In all cases the solute/solvent interface was determined using a molecular shape algorithm.11-15 Standard van der Waals radii (C ) 1.5 Å; N ) 1.5 Å; O ) 1.4 Å; H ) 1.2 Å; H(bound to polar atoms) ) 0.8 Å) were used. Scaling factors of 1.2 and 1.8 were used for water and CCl4, respectively. Since the change of the molecular geometry upon solvation has a negligible effect on the thermodynamic parameters only gasphase optimized geometries were used.2,20,21 Previous studies indicated that the root-mean-square deviations between experimental and MST/AM1 ∆Gsolv are 1.0 and 0.40 kcal/mol for aqueous14 and CCl415 solutions, respectively. The conformational free energy differences in solution were estimated by adding ∆∆Gsolv to the relative energies in the gas phase. Ab initio calculations were carried out using the Gaussian92 program.22 Solvation calculations were performed with an adapted version of MOPAC93 Revision 2 program,23 which permits MST calculations with H2O and CCl4 solvents. Calculations were carried out on a CRAY-YMP of the Centre de Supercomputacio´ de Catalunya (CESCA) and on a CONVEX C3480 of the Centre Europeu de Paral.lelisme de Barcelona (CEPBA). Results 2,4-Pentanedione. Nine energy minima could be predicted from the multiconformational analysis considering the two C-C(dO)-C-C(dO) dihedral angles of 6. All these were taken as starting points in ab initio HF/6-31G(d) geometry optimizations. However, only four equivalent and isoenergetic minima were characterized for 6, giving values for the C-C(dO)-C-C(dO) and C(dO)-C-C(dO)-C dihedral angles of 77.9°, 164.3°; 164.3°, 77.9°; -77.9°, -164.3°; -164.3°, -77.9°. One of the minimum energy conformations is displayed in Figure 1a. This compound has a parallel in 4a which was recently investigated at the same computational level.5,24 Four equivalent and isoenergetic minima were also found for such a compound, the N-C(dO)-C-C(dO) and C(dO)-C-C(dO)-N dihedral angles being 52°, 111°; 111°, 52°; -52°, -111°; -111°, -52°. In Figure 1b one of the minimum energy conformations is shown. It is immediately obvious that the diamide is stabilized by a six-membered hydrogen-bonded system. The asymmetric behavior of 4a was attributed to the formation of such

Comparison between Diketones and Diamides

J. Phys. Chem., Vol. 100, No. 40, 1996 16133

TABLE 1: Selected Torsional Anglesa (deg) and Relative Energiesb (kcal/mol) of the 2,5-Hexanedione (7) Minimum Energy Conformations C-C(dO)-C-C C(dO)-C-C-C(dO) C-C-C(dO)-C ∆E (HF/6-31G(d)//HF/6-31G(d)) ∆E (HF/6-31G(d)//HF/6-31G(d))c ∆E (MP2/6-31G(d)//HF/6-31G(d)) ∆E (MP2/6-31G(d)//HF/ 6-31G(d))c

TGT

TTT

-163.5 67.1 -163.5 0.0 0.0 0.0 0.0

180.0 180.0 180.0 1.0 0.8 1.7 1.5

a From ab initio HF/6-31G(d) geometry optimizations. b Level of energy calculation // level of geometry optimization. c Zero-point energy and thermal corrections computed at the HF/6-31G(d) level are included.

intramolecular hydrogen bond which disturbs the internal symmetry of the system.5,24 However, the minimum energy structures of 6 also give different values for the two central dihedral angles. Accordingly, these results suggests that the asymmetric behavior of 4a cannot be explained in terms of intramolecular interactions. 2,5-Hexanedione. Due to the chemical symmetry of 7, only 18 of the 27 theoretical conformations predicted by the multiconformational analysis were taken as starting points in geometry optimizations. Two different minima were found and characterized after a conformational search at the HF/6-31G(d) level of 7. Conformational angles and relative energies for such structures are shown in Table 1. The lowest energy minimum is shown in Figure 2a and corresponds to a TGT conformation in which the central methylene unit is folded. This conformation has a symmetric behavior on the two C-C(dO)-C-C dihedral angles as it is expected from the chemical and molecular symmetry of the compound. An equivalent and isoenergetic minimum with torsional angles 163.4, -67.2, 163.4 has also been found (data not shown). Another minimum corresponds to an all-trans conformation (Figure 2b) which is calculated to be about 0.8 kcal/mol less stable than the folded minimum in the gas phase. Single-point MP2/6-31G(d) calculations on the HF/6-31G(d) geometries increase the relative energy between the two conformations to 1.5 kcal/mol. To investigate the effect of the solvent on the stability of the two minima, we computed the free energies of solvation in both aqueous and CCl4 solutions. Results are displayed in Table 2, where the electrostatic and steric (van der Waals and cavitation) contributions to ∆Gsol are also included. Notice that values of ∆Gsolv are lower in CCl4 solution than in aqueous solution, indicating a higher affinity of 7 by organic solvents rather than by polar solvents. Solvents with different characteristics have a contrary effect on the relative estability of the two conformations. Thus, the effect of a polar solvent like water is very small, estabilizing the folded conformation TGT by 0.2 kcal/mol. On the contrary, the relative energy of the TTT conformation decreases from 1.5 kcal/mol in the gas phase to 1.1 kcal/mol in CCl4 solution. An inspection to the different contributions to ∆Gsol reveals that both the polarity and electronic structure of the solvent play a key role on the different behavior of aqueous and CCl4 solutions. However, the values of ∆∆Gsolv are too small to change the relative order between the two conformations. Ab initio HF/6-31G(d) geometry optimizations on the potential energy surface of 1a revealed the existence of five energy minima2 for the diamide analogue of 7. The lowest energy conformation corresponds to a C7 (intramolecular sevenmembered hydrogen-bonded system inducing) with the central dihedral angles N-C(dO)-C-C, C(dO)-C-C-C(dO) and

Figure 2. TGT (a) and TTT (b) minimum energy conformations of 2,5-hexanedione (7) and lowest energy (c) and X-ray determined (d) conformations of N,N′-dimethylsuccinamide (1a).

TABLE 2: Electrostatic and Steric (Cavitation + van der Waals) Contributions to the Free Energies of Solvation (∆Gsol) of 2,5-Hexanedione (7) in Aqueous and CCl4 Solutionsa solvent

conformer

∆Gele

∆Gsteric

∆Gsol

∆∆Gsol

∆Gconf

H2O

TGT TTT TGT TTT

-8.3 -8.0 -0.9 -0.8

3.1 3.0 -5.4 -5.9

-5.2 -5.0 -6.3 -6.7

0.0 0.2 0.4 0.0

0.0 1.7 0.0 1.1

CCl4

a Conformational free energy differences (∆Gconf) were computed by adding ∆∆Gsol to the best estimates of relative energies in the gas phase. All values are in kcal/mol.

C-C-C(dO)-N ≈ -169.7°, 73.9°, and -101.5°, respectively. In addition, three equivalent and isoenergetic minima with N-C(dO)-C-C and C-C-C(dO)-N ≈ 169.7°, 101.5°; 101.5, 169.7°; -101.5°, -169.7° were also found. It is worth noting that the torsional angle around the central methylene units adopts a G conformation in such minima (Figure 2c). The alltrans conformation was also characterized as the energy minimum for 1a, being 3.7 kcal/mol less stable than the folded conformation at the MP2/6-31G(d) level. The molecular structure determined for the N,N′-succinylbis(N′-propylglycinamide) (1, R ) -NHCH2CONHCH2CH2CH3) by X-ray crystallography3 is not a local minimum on the HF/6-31G(d) potential energy surface of 1a. The values for the central

16134 J. Phys. Chem., Vol. 100, No. 40, 1996

Alema´n et al. TABLE 4: Electrostatic and Steric (Cavitation + van der Waals) Contributions to the Free Energies of Solvation (∆Gsol) of 2,6-Heptanedione (8) in Aqueous and CCl4 Solutionsa solvent

conformer

∆Gele

∆Gsteric

∆Gsol

∆∆Gsol

∆Gconf

H2O

TGGT TTTT TGGT TTTT

-8.3 -9.9 -0.8 -1.2

3.1 3.2 -5.9 -6.4

-5.2 -6.7 -6.7 -7.6

1.5 0.0 0.9 0.0

0.0 0.2 0.0 0.8

CCl4

a Conformational free energy differences (∆Gconf) were computed by adding ∆∆Gsol to the best estimates of relative energies in the gas phase. All values are in kcal/mol.

Figure 3. Lowest energy conformations of (a) 2,6-heptanedione (8) and (b) N,N′-dimethylglutaramide (3a).

TABLE 3: Selected Torsional Anglesa (deg) and Relative Energiesb (kcal/mol) of the 2,6-Heptanedione (8) Minimum Energy Conformations C-C(dO)-C-C C(dO)-C-C-C C-C-C-C(dO) C-C-C(dO)-C ∆E (HF/6-31G(d)//HF/6-31G(d)) ∆E (HF/6-31G(d)//HF/6-31G(d))c ∆E (MP2/6-31G(d)//HF/6-31G(d)) ∆E (MP2/6-31G(d)//HF/ 6-31G(d))c

TGGT

TTTT

175.8 -68.6 -68.6 175.8 0.0 0.0 0.0 0.0

-179.8 180.0 180.0 -179.9 1.3 1.1 1.9 1.7

a From ab initio HF/6-31G(d) geometry optimizations. b Level of energy calculation // level of geometry optimization. c Zero-point energy and thermal corrections computed at the HF/6-31G(d) level are included.

dihedral angles in such a conformation are 172.2°, 75.3°, and 172.2° (Figure 2d), and it is 2.7 kcal/mol less stable than the lowest energy conformation.2,3 This conformation is estabilized by the formation of infinite networks of hydrogen bonds in the crystal. It is worth noting that the conformational angles found for N,N′-succinylbis(N′-propylglycinamide) deviate less than 10° from those predicted for 7. SCRF calculations indicate that aqueous solvent does not play any relevant role on the conformational preferences of 1a, changing the relative energy between the global minimun and all-trans conformation from 3.7 to 2.6 kcal/mol.2 Notice that the relative energy between the TGT and TTT conformations is similar in both 7 and 1a, being 1.5 and 1.0 kcal/mol, respectively, at the MP2/6-31G(d) level. 2,6-Heptanedione. Quantum mechanical calculations were also performed on 8, which is the diketone analogue of the diamide 2a. The large number of rotational degrees of freedom in this compound precludes a complete investigation of its conformational space. Thus, only two minimum energy structures were investigated. These correspond to TGGT (Figure 3a) and TTTT conformations. Conformational angles and energies are shown in Table 3. It is worth noting that the folded conformation was 1.1 l and 1.7 kcal/mol more favored than the all-trans conformation at the HF and MP2 levels, respectively. The ∆Gsolv for the two minimum energy conformations of 8 are displayed in Table 4. In this case the solute also has a higher affinity for organic solvents than for aqueous solvent. Results indicate that the TGGT conformation is less solvated than the TTTT one by 1.5 and 0.9 kcal/mol in aqueous and CCl4

solutions, respectively. Thus, the stability of the folded conformation with respect to the all-trans is decreased to -0.4 kcal/mol (HF/6-31G(d)) and 0.2 kcal/mol (MP2/6-31G(d)) in aqueous solution and to 0.5 kcal/mol (HF/6-31G(d)) and 0.8 kcal/mol (MP2/6-31G(d)) in CCl4 solution. These results suggest that TGGT and TTTT conformations tend to be isoenergetic in polar environments, whereas in low-polarity solvents, the former conformation would be slightly favored. Comparison between the all-trans conformers of 6 and 8 indicates that for the latter the small interactions between the carbonyl groups are screened by the solvent, whereas for the former such unfavorable interactions do not allow the existence of the extended conformation. The different behavior found for 7 and 8 in aqueous solution can be explained in terms of electrostatic interactions between the solute and the solvent. An analysis of the different energy contributions to ∆Gsolv reveals that for 8 the electrostatic term of the TTTT conformation is favored by 1.6 kcal/mol with respect to that of the TGGT conformer, whereas the van der Waals term was similar for the two conformers. On the other hand, results for 7 indicate that the TTT conformer is unfavored from an electrostatic point of view since the even number of methylene units produces a molecular dipole moment of 0.0 D. Only two minimum energy structures were found for 2a after a conformational search.1 These correspond to TSTTST (S denotes a skew conformation) and TTGGTT conformations, the latter being 1.9 kcal/mol more favored than the former at the HF/6-31G(d) level. Furthermore, the torsional angles for the folded conformation were almost equal to those found experimentally for N,N′-dipropylglutaramide (2, R ) -CH2CH2CH3). The TTTTT conformation was not found as an energy minimum on the potential energy hypersurface of 2a and was less stable than the folded conformation by 2.7 kcal/mol. The energy difference between the all-trans and the folded conformations is about 1 kcal/mol less favorable for the diamide than for the diketone. This should be attributed to the fact that the repulsive interaction energy between the two oxygen atoms is stronger for the former than for the latter. Thus, the electron distribution reorganization in the direction H f N f C f O induces a larger electron charge density in the oxygen atom of the amide group than in that of the keto group. 2-Hexanone. This molecule provides an opportunity to investigate the effect of the second carbonyl group on the folding of methylene units. Table 5 summarizes the main dihedral angles and relative energies of all the minimum energy conformations found at the HF/6-31G(d) level. The effect of electron correlation on relative energies is expected to be very small in 9 and therefore calculations were performed only at the SCF level.9 Notice that the global minimum corresponds to the extended conformation TTT, which is 0.3 kcal/mol favored with respect to the folded structure TGT. Thus, the two conformations are almost isoenergetic, whereas at the same level of theory, the folded form was found 0.8 and 1.1 kcal/

Comparison between Diketones and Diamides

J. Phys. Chem., Vol. 100, No. 40, 1996 16135

TABLE 5: Selected Torsional Anglesa (deg) and Relative Energies (kcal/mol) of the 2-Hexanone (9) Minimum Energy Conformations C-C(dO)-C-C C(dO)-C-C-C C-C-C-C ∆E TTT TGT TTG GTT TGG GGT GTG GGG

180.0 -168.1 -179.6 97.8 -167.8 62.5 98.1 82.3

180.0 72.0 176.1 178.7 70.0 62.5 175.5 59.0

180.0 179.3 65.9 180.4 66.3 178.0 66.0 60.3

0.0 0.2 1.0 1.2 1.4 1.9 2.2 2.4

∆Eb 0.0 0.3 1.1 1.4 1.5 2.1 2.5 2.7

a From ab initio HF/6-31G(d) geometry optimizations. b Zero-point energy and thermal corrections computed at the HF/6-31G(d) level are included.

TABLE 6: Electrostatic and Steric (Cavitation + van der Waals) Contributions to the Free Energies of Solvation (∆Gsol) of 2-Hexanone (9) in Aqueous Solutiona conformer

∆Gele

∆Gsteric

∆Gsol

∆∆Gsol

∆Gconf

TTT TGT TTG GTT TGG GGT GTG GGG

-5.8 -5.7 -5.8 -6.1 -5.7 -6.0 -6.1 -6.2

2.6 2.6 2.6 2.7 2.5 2.7 2.7 2.7

-3.2 -3.1 -3.2 -3.4 -3.2 -3.3 -3.4 -3.5

0.3 0.4 0.3 0.1 0.3 0.2 0.1 0.0

0.0 0.4 1.1 1.2 1.5 2.0 2.3 2.4

a Conformational free energy differences (∆Gconf) were computed by adding ∆∆Gsol to the relative energies in the gas phase. All values are in kcal/mol.

TABLE 7: Electrostatic and Steric (Cavitation + van der Waals) Contributions to the Free Energies of Solvation (∆Gsol) of 2-Hexanone (9) in CCl4 Solutiona conformer

∆Gele

∆Gsteric

∆Gsol

∆∆Gsol

∆Gconf

TTT TGT TTG GTT TGG GGT GTG GGG

-0.6 -0.5 -0.5 -0.6 -0.5 -0.6 -0.6 -0.6

-5.0 -5.0 -4.9 -5.1 -4.6 -4.6 -5.1 -5.0

-5.6 -5.5 -5.4 -5.7 -5.1 -5.2 -5.7 -5.6

0.1 0.2 0.3 0.0 0.6 0.5 0.0 0.1

0.0 0.4 1.3 1.3 2.0 2.5 2.4 2.7

a Conformational free energy differences (∆Gconf) were computed by adding ∆∆Gsol to the relative energies in the gas phase. All values are in kcal/mol.

mol more favored than the all-trans one in diketones 7 and 8, respectively. This is a very interesting feature since it suggests that the folding of methylene units only occurs when the aliphatic segment is between two carbonyl groups. The results indicate that the two carbonyl groups of diamides and diketones produce a concerted and simultaneous effect on the central methylene units. Six additional minima were predicted for 9, the relative energies of which range from 1.1 to 2.7 kcal/mol. Free energies of solvation in aqueous and CCl4 solutions are reported in Tables 6 and 7, respectively. It is worth noting that both polar and organic solvents have a small effect on the conformational equilibrium of 9. Thus, the larger values of ∆∆Gsol were 0.4 and 0.6 kcal/mol for aqueous and CCl4 solutions, respectively. As in 7 and 8 the solute presents a higher affinity for CCl4 than for water. Solvents do not introduce any change in the relative order between the different conformers. Thus, in the two environments, the TGT conformation was 0.4 kcal/mol unfavored with respect to the TTT one, which indicates a destabilization of only 0.1 kcal/mol with respect to the gas-phase results.

Concluding Remarks The results presented in this paper give a detailed picture of the folding of methylene units in diketones with a central aliphatic segment comprised by three or less methylene groups. The comparison with the results obtained in previous works for related diamides leads to relevant conclusions on the understanding of this conformational behavior. (i) The allowed conformational space of compounds with an isolated methylene unit is very restricted. Thus, an unique minimum energy conformation was found and characterized for both 4a and 6. Both the similarity between the minimum energy conformations of the two compounds and the fact that 6 cannot form intramolecular hydrogen bonds like 4a indicate that the unusual asymmetric conformational preferences of 4a and 6 are mainly due to the repulsive interactions between the two oxygen atoms. (ii) The lowest energy conformations of both diamide and diketone compounds with two or three methylene units between the carbonyl groups present a folding in the aliphatic segment. More specifically, the central methylene units adopt a G conformation. Despite their important chemical and physical differences, the two families of compounds present a strong parallelism in their conformational behavior. Furthermore, a comparison between the relative energies between the folded conformation and the second favored energy minimum in diketones and diamides indicates that the dipole moment of the amide group tends to favor the folding of methylene units. (iii) The effects of the solvent on the conformational preferences of diketones and diamides have been computed in this and previous works by means of SCRF methods. From a quantitative point of view, caution must be taken due to the existence of source of errors, such as the incomplete representation of specific solute-solvent interactions. However, the results strongly suggest that the solvent does not have any relevant influence on the folding of methylene units. This is a very surprising result since previous studies on nonmodified amino acids, i.e. those without a retroinversion in the first amide group, clearly indicate that polar solvents such as water induce a drastic change in their conformational preferences.21,25,26 (iv) Ab initio calculations on a compound with only one keto group reveal that the conformations with the central methylene units in T and G are almost isoenergetics, the former being 0.3 kcal/mol more favored than the latter. This is the result that must be expected a priori for such kind of compounds. This feature suggests that the folding of methylene units only appears in those compounds in which the aliphatic segment is located between two carbonyl groups. Acknowledgment. The authors express their gratitude to Drs. M. Orozco and F. J. Luque for making available to us their version of MOPAC93 adapted to perform MST calculations. The research was supported by a DGICYT project No. PB931067. Authors are indebted to Centre de Supercomputacio´ de Catalunya (CESCA) and Centre Europeu de Paral.lelisme de Barcelona (CEPBA) for computationl facilities. References and Notes (1) Navarro, E.; Alema´n, C.; Puiggalı´, J. J. Am. Chem. Soc. 1995, 117, 7307. (2) Alema´n, C.; Navarro, E.; Puiggalı´, J. J. Org. Chem. 1995, 60, 6135. (3) Navarro, E.; Tereshko, V.; Subirana, J. A.; Puiggalı´, J. Biopolymers 1995, 36, 711. (4) Alema´n, C.; Pe´rez, J. J. J. Mol. Struct. 1993, 285, 221. (5) Alema´n, C.; Puiggalı´, J. J. Org. Chem. 1995, 60, 910.

16136 J. Phys. Chem., Vol. 100, No. 40, 1996 (6) Bunn, C. W. Chemical Crystallography; Oxford University Press: Oxford U.K., 1946. (7) (a) Alema´n, C.; Vega, M. C.; Navarro, E.; Puiggalı´, J. J. Pept. Sci. 1996, in press. (b) Vega, M. C.; Alema´n, C.; Navarro, E.; Puiggalı´, J. Submitted for publication. (8) Karle, I.; Flippen-Anderson, J. L.; Agarwalla, S.; Balaram, P. Proc. Natl. Acad. Sci. U.S.A. 1991, 88, 5307. (9) Wiberg, K. B.; Martin, E. J. Am. Chem. Soc. 1985, 107, 5035. (10) Berry, R. J.; Waltman, R. J.; Pacansky, J.; Hagler, A. T. J. Phys. Chem. 1995, 99, 10511. (11) Miertus, S.; Scrocco, E.; Tomasi, J. Chem. Phys. 1981, 55, 117. (12) Miertus, S.; Tomasi, J. Chem. Phys. 1982, 65, 239. (13) Negre, M. J.; Orozco, M.; Luque, F. J. Chem. Phys. Lett. 1992, 196, 27. (14) Luque, F. J.; Negre, M. J.; Orozco, M. J. Phys. Chem. 1993, 97, 4386. (15) Luque, F. J.; Alema´n, C.; Bachs, M.; Orozco, M. J. Comput.Chem. 1995, in press. (16) Hariharam, P. C.; Pople, J. A. Theor. Chim. Acta 1973, 28, 203. (17) Møller-Plesset, M. S. Phys. ReV. 1934, 46, 618. (18) Pierotti, R. A. Chem. ReV. 1976, 76, 717.

Alema´n et al. (19) (a) Ferenczy, G. G.; Reynolds, C. A.; Richards, W. G. J. Comput. Chem. 1990, 11, 159. (b) Alhambra, C.; Luque, F. J.; Orozco, M. J. Comput.Chem. 1994, 15, 12. (20) Orozco, M.; Luque, F. J. J. Am. Chem. Soc. 1995, 117, 1378. (21) Alema´n, C. Int. J. Pept. Protein Res. 1995, 46, 408. (22) Gaussian-92, Revision F.4.: Frisch, M. J.; Trucks, G. W.; HeadGordon, M.; Gill, P. M. W.; Wong, M. W.; Foresman, J. B.; Johnson, B. G.; Schlegel, H. B.; Robb, M. A.; Replogle, E. S.; Gomperts, R.; Andres, J. L.; Ragahavachari, K.; Binkley, J. S.; Gonza´lez, C.; Martin, R. L.; Fox, D. J.; Defrees, D. J.; Baker, J.; Stewart, J. J. P.; Pople, J. A. Gaussian, Inc., Pittsburgh, PA, 1992. (23) Stewart, J. J. P. MOPAC 93, Revision 2; Stewart Comp. Chem, 1994. Adapted to perform MST calculations by F. J. Luque and M. Orozco. (24) Alema´n, C.; Pe´rez, J. J. J. Mol. Struct. (THEOCHEM) 1993, 285, 221. (25) Bonnacorsi, R.; Palla, P.; Tomasi, J. J. Am. Chem. Soc. 1984, 106, 1945. (26) Shang, H. S.; Head-Gordon, T. J. Am. Chem. Soc. 1994, 116, 1528.

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