Ab initio conformational analysis of α-aminoaldehydes and α-aminoketones in the gas phase and in aqueous solution

Ab initio conformational analysis of a-aminoaldehydes anda-aminoketones in the gas phase and in aqueous solution

Luis Carballeira*, Ignacio PeÂrez-Juste

Departamento de Quimica Fisica, Universidad de Vigo, Apdo. 874, 36200 Vigo, Spain

Received 1 December 1997; accepted 14 April 1998

Abstract

The ab initio conformational analysis of 10 a-aminoaldehydes and a-aminoketones containing the N±C±CyO moiety was

carried out at the HF/3-21G, HF/6-31G** and MP2/6-31G** levels. Conformational preferences are mainly interpreted in terms

of different kinds of intramolecular hydrogen bonding, although other effects should also be considered. These effects explains the

energetic and geometrical differences observed between N±C±CyO and related C±C±CyO compounds. Finally, by means of an

ab initio method for the treatment of the solvent as a continuum (polarizable continuum model, PCM), the in¯uence of water on

the conformational stabilities was estimated. Signi®cant changes in relative energies were found, which were related to the

interaction between the dipole moment of the solute and the reaction ®eld of the solvent, although local dipolar interactions or the

presence of hydrogen bonding in certain conformations can also be important. q 1998 Elsevier Science B.V. All rights reserved.

Keywords: Ab initio calculations; Conformational analysis; N±C±CyO unit; Hydrogen bonding; In¯uence of water

1. Introduction

As the smallest amino acid, glycine (GLY) is very

important in the formation of peptides, the backbone

of proteins. For this reason, this compound has been

the object of numerous experimental and theoretical

studies [1±15]. After some initial controversy, micro-

wave and electron diffraction spectra con®rmed the ab

initio prediction about the most stable conformer of

GLY, which is characterized by a bifurcated hydrogen

bonding interaction between the hydrogen of the

amino group and the carbonylic oxygen. However,

very little attention has been devoted to some related

molecules, such as a-aminoaldehydes or a-aminoke-

tones, which also display the N±C±CyO unit present

in amino acids. These compounds have not been

characterized experimentally and only 2-amino-

ethanal (2AE), the smallest a-aminoaldehyde, has

been studied by theoretical methods. Vishveshwara

and Pople [1] compared the HF/4-31G conformational

maps of GLY and 2AE obtained using standard

geometries. Peters and Peters [16] employed their

STO-3G and HF/4-31G results for estimating the

conformational preferences of peptides and proteins.

Both papers suggested the importance of intramolecu-

lar hydrogen bonding on the conformational prefer-

ences of 2AE or GLY. Van Alsenoy and co-workers

[17] studied the rotational barrier of 2AE by means of

HF/4-21G calculations and compared their results

with those for the methyl ester of glycine. More

recently, we have carried out a complete conforma-

tional analysis of 2AE and some derivatives both at

the HF/6-31G** and MP2/6-31G* levels [18, 19],

paying special attention to the rotational barrier of

the N±C±CyO unit and the presence of ¯at energy

Journal of Molecular Structure (Theochem) 453 (1998) 233±245

0166-1280/98/$ - see front matter q 1998 Elsevier Science B.V. All rights reserved.

PII: S0166-1280(98)00204-8

* Corresponding author. Tel.: +34 86 812306; fax: +34 86

812382; e-mail: [email protected]

valleys in the range between 150 and 1808, which may

be related to the ¯exibility of peptides and proteins.

In order to complete these previous studies, we

present in this paper the global ab initio conforma-

tional analysis of a series of 10 molecules directly

related to GLY, 2AE being the parent compound of

the group. All these compounds display the N±C±

CyO unit, which is a focal point of our research

since ab initio data are needed for the development

of molecular mechanics parameters [18]. The in¯u-

ence of several types of intramolecular hydrogen

bonding, dipole±dipole interactions and eclipsing

between different bonds on the conformational

stabilities of these compounds will be discussed.

Furthermore, as the biological compounds in which

the N±C±CyO unit is included are usually in solution,

L. Carballeira, I. PeÂrez-Juste / Journal of Molecular Structure (Theochem) 453 (1998) 233±245234

Fig. 1. Notation employed for the compounds studied. Newman projections along C3±N4 (a) and C2±C3 (b) bonds. The representation

corresponds to a CG form

the in¯uence of water on the conformational stabilities

has been estimated by means of an ab initio method

for the treatment of a solute embedded in a dielectric

continuum solvent (polarizable continuum model,

PCM) [21±23].

2. Method

The compounds studied in this work are shown

schematically in Fig. 1. The smallest compound of

the series, 2-aminoethanal, is related to GLY by

substitution of the hydroxy group for a hydrogen

atom. The a-aminoketones are obtained replacing

the hydroxy by a methyl group, 1-amino-2-propanone

(1A2PN) being the smallest ketone of the series. By

means of mono- and bimethylations of these parent

compounds we obtained all the compounds displayed

in Fig. 1. A two-letter notation is adopted for charac-

terizing the conformers: the ®rst letter represents the

value of the N4±C3±C2yO1 torsional angle as C(08),G(608), E(1208), T(1808), E 0(21208) and G 0(2608),and the second letter is related to the R9±N4±C3±C2

torsion. The angles indicated are round ®gures, and

they do not coincide exactly with the values for opti-

mized geometries.

For locating the stable conformers, as in previous

studies [18, 19], we obtained the rotational potential

energy curves for the N±C±CyO torsions by means

of restricted optimizations, ®xing the value of the

dihedral angles between 0 and 360. Conformations

around regions of minimum energy were freely opti-

mized, and then characterized as minima by means of

the analysis of their vibrational frequencies. Geome-

trical optimizations were carried out at the Hartree±

Fock (HF) level employing 3-21G and 6-31G** basis

sets. The in¯uence of electron correlation was esti-

mated by MP2/6-31G** single-point calculations at

the optimized HF/6-31G** geometries. For some

compounds, MP2/6-31G** geometrical optimizations

were also performed. Throughout the whole study the

gaussian 94 [24] program was used.

The in¯uence of water was estimated using an ab

initio solvation procedure based on a continuous

description of the solvent (Polarizable Continuum

Model, PCM) [21±23] whose reliability has been

widely checked. The 6-31G** basis set was used,

with the gas phase geometries optimized at the same

L. Carballeira, I. PeÂrez-Juste / Journal of Molecular Structure (Theochem) 453 (1998) 233±245 235

Table 1

HF/3-21G, HF/6-31G** and single-point MP2/6-31G** relative energies (in kcal mol21) for the stable conformers of the compounds studied

2AE 1A2PN 2MAE 2AP 2DMAE

3-21G 6-31G** MP2 3-21G 6-31G** MP2 3-21G 6-31G** MP2 3-21G 6-31G** MP2 3-21G 6-31G** MP2

CG 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.85 0.00 0.00 0.06 1.02 0.42

EG 2.38 3.22 3.29 1.75 1.85 2.24 1.79 1.78

TG 1.61 2.31 2.61 2.25 2.52 2.68

E 0G 1.83 1.74 1.56

CG 0 1.72 1.75 1.74 1.77 0.68 0.34 0.63 1.39 1.13 1.11 1.90 1.73 0.90

EG 0 0.49 1.39 2.06 0.96 1.91 2.14 0.71 0.56 1.40 1.24 1.03 1.51 0.00 0.00 0.00

CT 2.11 2.17 2.00 1.77 1.83 1.61

E 0T 0.05 0.44 1.00 0.00 0.55 0.82

2M2AP 2R2MAP 2S2MAP 3A2BN 1MA2PN

3-21G 6-31G** MP2 3-21G 6-31G** MP2 3-21G 6-31G** MP2 3-21G 6-31G** MP2 3-21G 6-31G** MP2

CG 0.68 0.00 0.00 2.09 1.52 0.77 0.00 0.00 0.00 0.96 0.00 0.00 0.00 0.00 0.00

EG 1.46 1.27 1.01 2.52 2.41 1.85 1.73 1.44 1.71 2.25 2.21 2.44 2.51 2.90 2.99

E 0G 1.69

CG 0 1.41 1.63 1.45 2.03 1.82 1.28 0.42 0.46 0.32 2.16 1.36 1.23 1.02 0.25 0.58

EG 0 0.00 0.71 0.93 0.00 0.32 0.31 2.23 2.02 2.31 1.27 1.04 1.31 1.20 1.18 1.70

CT 2.66 2.21 1.43 3.43 4.30 3.98 2.23 1.11 1.02 2.78 2.86 2.78

E 0T 0.50 0.00 0.00 0.05 1.27 1.45 0.00 0.58 0.89 0.57 1.12 1.32


Tab

le2

Sel

ecte

dH

F/6

-31

G**

geo

met

rica

lp

aram

eter

sfo

rth

est

able

confo

rmer

sof

the

com

pounds

studie

d

2A

E1A

2P

N

CG

TG

CG0

EG0

CG

EG

CG0

EG0

N4

±C

3±

C2

±O

10

.00

18

0.0

01

1.7

6152.2

50.0

0154.4

814.4

3144.9

6

R8

±N

4±

C3

±C

22

58

.69

26

1.7

02

16

6.3

0166.2

92

58.2

82

60.3

12

164.4

9166.7

8

R9

±N

4±

C3

±C

25

8.6

96

1.7

02

43

.94

273.5

958.2

863.4

72

42.1

52

74.0

0

H8zzz

O1

2.7

77

72.7

204

H9zzz

O1

2.7

77

72

.451

62.7

204

2.3

724

2M

AE

2A

P

CG

EG

CG0

EG0

CT

E0 T

CG

EG

E0 G

CG0

EG0

CT

E0 T

N4

±C

3±

C2

±O

12

3.4

21

49

.58

9.0

9149.5

62

2.7

12

144.1

12

1.8

3128.5

72

129.4

411.1

1139.0

12

13.8

32

139.1

0

R8

±N

4±

C3

±C

22

73

.29

26

4.7

42

16

9.3

8171.1

873.2

876.8

22

57.1

82

60.8

42

58.7

02

163.7

1170.3

844.3

474.8

3

R9

±N

4±

C3

±C

25

1.4

56

3.7

92

41

.93

264.9

72

161.9

22

158.5

259.3

461.3

762.4

42

41.2

82

69.8

0166.8

62

165.7

2

H8zzz

O1

2.7

149

2.4

160

H9zzz

O1

2.6

82

22

.444

02.7

206

2.3

979

2D

MA

E2M

2A

P

CG

TG

CG0

EG0

CG

EG

CG0

EG0

N4

±C

3±

C2

±O

10

.00

18

0.0

01

.90

150.7

60.0

0125.4

219.4

4134.3

9

R8

±N

4±

C3

±C

22

67

.14

26

7.5

41

62

.20

159.8

52

58.1

82

62.0

32

161.8

1165.1

6

R9

±N

4±

C3

±C

26

7.1

46

7.5

42

70

.40

272.8

458.1

860.2

12

40.1

52

75.2

5

H8zzz

O1

2.6

934

H9zzz

O1

2.6

934

2.3

286

2R

2M

AP

2S

2M

AP

CG

EG

CG0

EG0

CT

E0 T

CG

EG

CG0

EG0

CT

E0 T

N4

±C

3±

C2

±O

12

9.7

31

41

.42

20

.01

139.4

80.7

72

143.9

42

12.2

8138.6

512.4

0140.4

52

6.0

32

143.1

0

R8

±N

4±

C3

±C

22

71

.43

26

2.1

32

17

6.7

7157.8

871.4

275.8

52

73.8

72

64.2

02

151.6

82

179.2

172.8

475.3

2

R9

±N

4±

C3

±C

25

2.0

26

5.4

62

45

.74

276.0

72

163.9

02

159.1

949.5

963.7

72

25.1

02

56.3

62

159.9

62

157.6

7

H8zzz

O1

H9zzz

O1

2.5

97

72

.400

22.5

640

2.2

442


3A

2B

N1M

A2P

N

CG

EG

CG0

EG0

CT

E0 T

CG

EG

CG0

EG0

CT

E0 T

N4

±C

3±

C2

±O

12

6.3

31

46

.75

14

.34

150.8

62

38.3

72

109.3

82

12.6

6138.7

820.8

0143.4

02

10.3

92

142.8

4

R8

±N

4±

C3

±C

22

57

.99

25

8.3

82

15

6.0

6167.9

547.5

773.8

12

74.8

92

65.5

82

164.2

0169.6

076.6

180.0

4

R9

±N

4±

C3

±C

25

7.7

86

5.2

12

33

.98

272.6

5168.2

32

167.1

348.0

163.9

12

37.4

12

67.2

92

158.8

62

155.5

2

H8zzz

O1

2.6

97

42.3

618

H9zzz

O1

2.6

22

02

.24

46

2.5

338

2.3

145

level. According to this model, the solvation energy

for a solute M, DGsol, which has the status of free

energy, can be split into the following terms:

DGsol�M� � W�M�1 DGther 1 D�PV�The ®rst term represents the dipole±solvent inter-

actions, and the remaining terms are contributions due

to the motion of solute molecules and should require

the evaluation of vibrational, rotational, and transla-

tional partition functions of the solute M in the gas

phase and in solution. These last terms remain

approximately constant when considering energy

differences between conformations and can be

neglected [25, 26]. In this way, DGsol reduces to the

solute±solvent interaction term, which can be split

into

DGsol � DGel 1 DGno2el � DGel 1 DGcav 1 DGdis±rep

A detailed description of each term is out of the

scope of this paper, but it can be indicated that DGel

represents the electrostatic interaction between solute

and solvent, and the non-electrostatic term, DGno-el, is

formed by the cavitation energy, DGcav, calculated for

a cavity de®ned in terms of van der Waals spheres,

according to Pierotti equations [27], and a dispersive±

repulsive interaction, DGdis±rep, calculated according

to atom±atom coef®cients [28].

3. Results and discussion

3.1. In¯uence of the calculation level

Table 1 shows the relative energies for the stable

conformers of the series of compounds studied at

several computational levels. Some selected HF/6-

31G** optimized geometrical parameters are

displayed in Table 2. The torsional angles indicate

that energy minima always present staggered disposi-

tions of the amino group (G, G 0 or T), and N±C±CyO

angles located around 08 and ^1408, although the

values for several minima lie around 1808 and ^1208.The results of Table 1 allow us to analyze the in¯u-

ence of the calculation level on the conformational

preferences. At the HF level, remarkable differences

can be seen between the relative energies obtained

with the 3-21G and 6-31G** basis sets. Discrepancies

are not systematic, e.g. HF/3-21G and HF/6-31G**

energy orderings are equal in 2AE, 1A2PN or

2DMAE, but the relative energies are clearly differ-

ent. In other cases the energy order is different at both

HF levels (2MAE, 2S2MAP or 1MA2PN), and even

the most stable conformer is not the same (2AP,

2M2AP, 2R2MAP or 3A2BN). Furthermore, in

2AE, 1A2PN, 2AP and 2S2MAP, the number of char-

acterized minima with both methods is different.

Although it is dif®cult to ®nd a general rule, it

seems that the 3-21G basis set tends to destabilize

conformers with torsional angles around 08, or to

stabilize conformers with dihedrals close to ^1508.According to the MP2/6-31G** single-point ener-

gies, the effect of electron correlation seems to be

scarcely important in these compounds. Thus, HF/6-

31G** and MP2/6-31G** stabilities are quite similar,

although some signi®cant trends could be noted. For

instance, the CG/TG or CG/EG energy differences at

the MP2 level increase slightly (<0.3 kcal mol21)

with respect to the HF values in most cases (except

2M2AP and 2R2MAP). This could be related to the

stabilization of the CG conformers with intramolecu-

lar hydrogen bonding (see below). Reductions in the

energy differences (<0.5 kcal mol21) are also

observed for the pairs CG 0/EG 0 and CT/E 0T, where

electron correlation stabilizes the CG 0 and CT con-

formers, probably because the orientation of the

oxygen and nitrogen lone pairs changes due to the

rotation of the amino group (see Fig. 1). In any

case, variations in relative energy are usually not

larger than 0.5 kcal mol21.

Moreover, as it has been suggested that MP2 single-

point calculations at HF optimized geometries provide

inaccurate results [11, 29, 30], we have also carried

out the MP2/6-31G** geometry optimization of the

stable conformers of 2AE, 1A2PN, 2DMAE and

2M2AP, to determine whether correlated optimized

geometries alter the conformational stabilities. From

the results of Tables 1 and 3, it can be observed that

MP2 single-point and MP2 optimized relative ener-

gies are similar, which indicates that, for the current

molecules, single-point calculations are probably

enough to account for the effect of electron correla-

tion. With regard to the correlated geometries, the

most remarkable difference between HF and MP2

results is the reduction of the NH¼O distances.

This feature is accompanied by changes of several

degrees in the torsional angles involved, which


contribute to the shrinkage of the non-bonded lengths

(see Tables 2 and 3).

3.2. Conformational analysis

As was previously done for GLY [14] or a,a 0-diaminoacetone [20], it is tempting to discuss the

conformational preferences of the compounds studied

in terms of different types of hydrogen bonding, which

depend on the orientation of the amino group. Thus,

when the amino group is in the G disposition, there is

possibly a bifurcated intramolecular hydrogen bond-

ing NH2:::O, which closes two rings of ®ve atoms

(IHB1 in Fig. 2). According to the non-bonded

distances shown in Table 2, this IBH1 interaction is

symmetric in 2AE, 1A2PN, and 2M2AP, and slightly

distorted in 2AP and 3A2BN, due to the asymmetrical

methylation in the central C3 atom. The HF/6-31G**

average non-bonded distance for these bifurcated

interactions is 2.7138 AÊ .

When the amino group is methylated in R8 (2MAE,

2R2MAP, 2S2MAP and 1MA2PN), the CG confor-

mers lose their Cs symmetry, and only one ``simple''

NH¼O hydrogen bonding is possible (IHB2 in

Fig. 2). The existence of this interaction explains the

negative values of the N±C±CyO torsions, since in

this way the oxygen of the carbonyl and the amino

hydrogen H9 can get closer. As can be seen in Table 2,


Table 3

MP2/6-31G**//MP2/6-31G** relative energies (Er, in kcal mol21) and selected optimized parameters for the stable conformers of 2AE,

1A2PN, 2DMAE and 2M2AP

2AE 1A2PN

CG TG CG 0 EG 0 CG EG CG 0 EG 0

Er 0.00 2.61 1.62 2.11 0.00 3.24 1.48 2.13

N4±C3±C2±O1 0.00 180.00 14.89 150.19 0.00 145.77 20.91 146.73

R8±N4±C3±C2 256.36 259.01 2153.50 164.86 255.95 256.98 2153.44 166.86

R9±N4±C3±C2 56.36 59.01 235.16 278.26 55.95 61.52 235.82 277.20

H8zzzO1 2.7170 2.6682

H9zzzO1 2.7170 2.2944 2.6682 2.2402

2DMAE 2M2AP

CG TG CG 0 EG 0 CG EG CG 0 EG 0

Er 0.41 2.64 0.85 0.00 0.00 0.88 1.44 0.95

N4±C3±C2±O1 0.00 180.00 2.51 148.25 0.00 117.60 20.16 138.21

R8±N4±C3±C2 264.75 264.67 167.24 165.59 256.09 259.14 2157.99 168.51

R9±N4±C3±C2 64.75 64.67 270.07 271.58 56.09 57.98 240.40 275.88

H8zzzO1 2.6541

H9zzzO1 2.6541 2.2839

Fig. 2. Types of intramolecular hydrogen bonding in the N±C±CyO compounds

non-bonded distances in these CG minima displaying

an IHB2 interaction are notably smaller, the average

being 2.5944 AÊ .

For CG 0 and CT conformers, the rotation of the

amino group allows only for the interaction between

one amino hydrogen and the carbonylic oxygen. Non-

bonded distances (Table 2) con®rm the existence of

another ``simple'' NH¼O hydrogen bonding in these

forms (IHB3 in Fig. 2). All the CG 0 conformers show

negative N±C±CyO torsions, which deviate from 08more than in the CG minima to reduce non-bonded

lengths. The same happens in the CT conformers of

2AP and 3A2BN (the only ones that present H bond-

ing, see Fig. 1). The N±C±CyO torsions in these

minima are larger than in the other CT forms, where

the intramolecular interaction cannot occur. The aver-

age over the IHB3 NH¼O lengths in CG 0 and CT

conformers is 2.3614 AÊ .

The existence of hydrogen bonding can help to

explain the conformational stabilities, though other

effects should also be considered. Thus, in all those

cases where the bifurcated interaction IHB1 takes

place (2AE, 1A2PN, 2AP, 2M2AP, 3A2BN,

1MA2PN), the CG conformer is found to be the

most stable. The same happens for 2MAE and

2S2MAP, even though only one IHB2 interaction

occurs. 2DMAE-CG and 2R2MAP-CG are exceptions

to this behaviour, though for different reasons. In

2DMAE, the bimethylation of the amino group avoids

the existence of H bonding, and in 2R2MAP the steric

repulsions between adjacent methyl groups in R7 and

R8 (see Fig. 1(a)) notably destabilize the CG form.

With regard to the energy ordering, the CG/CG 0

energy differences in the symmetrical molecules

(2AE, 1A2PN, 2M2AP) are approximately 1.7 kcal

mol21 at the HF/6-31G** level. The CG 0 forms are

less stable than the CG ones for two reasons: (a) one

of the H bonds disappears due to the rotation of the

amino group, and (b) the relative orientation of the

oxygen and nitrogen lone pairs is less favourable,

which explains the larger dipolar moments of the

CG 0 minima (see Table 4). In this sense, the CG/

CG 0 energy difference for 2DMAE (<0.7 kcal

mol21), where none of the conformers can display

hydrogen bonding, should correspond to the destabi-

lization of the 2DMAE-CG 0 form, due to the inter-

action between lone pairs. It should also be noted that

the CG/CG 0 differences for 2AP and 3A2BN are

approximately 0.4±0.5 kcal mol21 lower than in the

symmetric molecules, what indicates that the CG

conformer is less stabilized if IHB1 is not symmetric.

For 2MAE, 2R2MAP, 2S2MAP and 1MA2PN, the

CG and CG 0 conformers show different types of

hydrogen bonding, IHB2 and IHB3, respectively,

and the CG/CG 0 energy differences are reduced by

up to 0.3 kcal mol21, less than that observed in

2DMAE due to the orientation of the lone pairs.

This suggests that IHB3 should be more effective

than IHB2, in accordance with the smaller NH¼O

non-bonded distances.

The origin of the CG/CT and CG/CG 0 energy

differences is similar. The CG/CT differences for

2AP and 3A2BN (1.8 and 1.1 kcal mol21, respec-

tively) should correspond to the loss of one H bond

(IHB1 ! IHB2), although the smaller value for

3A2BN could be due to the large N±C±CyO torsional

angle in CT (2388), which allows one to reduce the

NH¼O non-bonded length. The CG/CT differences

are higher for 2MAE and 1MA2PN (2.1 and 2.8 kcal -

mol21) because no H bonding is possible in CT. The

values for 2R2MAP and 2S2MAP (20.7 and

4.3 kcal mol21) depend strongly on the orientation of

the C3±Me and N4±Me groups (see Fig. 1). Thus,

CG is more stable in 2S2MAP and CT is more stable


Table 4

HF/6-31G** dipolar moments (in Debyes) for the stable conformers

of the compounds studied

2AE 1A2PN 2MAE 2AP 2DMAE

CG 1.89 2.33 1.94 2.04 2.04

EG 3.08 2.74 2.44

TG 2.61 2.92

E 0G 2.22

CG 0 3.39 3.44 3.09 3.33 3.31

EG 0 3.18 3.07 3.05 3.08 3.16

CT 3.65 3.46

E 0T 3.26 3.03

2M2AP 2R2MAP 2S2MAP 3A2BN 1MA2PN

CG 2.11 2.11 2.08 2.42 2.38

EG 2.27 2.53 2.64 2.92 3.05

CG 0 3.24 3.12 2.79 3.25 2.98

EG 0 3.07 3.09 2.91 3.07 3.03

CT 3.66 3.69 3.11 3.69

E 0T 3.26 3.14 2.88 3.29


Fig. 3. Schematic representation and energy differences for related N±C±CyO and C±C±CyO compounds

in 2R2MAP because in these forms both methyl

groups are in trans orientation, as far as possible.

The comparison between the results obtained for the

N±C±CyO compounds and the data available for

related compounds could help to con®rm the impor-

tance of H bonding in these molecules. For doing this,

we have considered the compounds shown in Fig. 3,

divided into two groups: on the left, those containing

the N±C±CyO unit; on the right, those containing a

C±C±CyO unit, where the amino is substituted by a

methyl group. For each series, different substituents in

the R5 position (H, Me, OH, OMe) were considered.

For all the compounds, two minima are located when

the amino or the methyl group is in G orientation: (a)

CG of Cs symmetry with the X±C±CyO torsion equal

to 08, and (b) TG or EG, for the N±C±CyO and C±C±

CyO compounds with central torsions of 180 and

1208, respectively. The energy differences between

conformers (CG/TG or CG/EG) follow the same

trend in both series of compounds, that is OH ,OMe , Me. This can be related to steric interactions

between the groups at both ends of the molecule,

which are probably of the same order in both series

of molecules. However, the CG/EG energy differences

in the C±C±CyO compounds are always smaller than

CG/TG in the N±C±CyO ones. These numerical

discrepancies seem to be related to H bonding,

because the C4±Me avoids the formation of H bond-

ing in the C±C±CyO compounds. Thus, for GLY, it

was suggested [14] that bifurcated H bonding existed

in the CG and TG forms (Fig. 4). Both non-bonded

interactions will also occur in MEG, what could

explain the similar CG/EG energy differences for

GLY and MEG ( < 1.90 kcal mol21). The energy

difference for 2AE increases (2.31 kcal mol21)

because 2AE-TG cannot display H bonding. For

1A2PN, the energy difference (3.22 kcal mol21) has

a similar origin, though the value is higher because

those conformations with N±C±CyO torsions close

to 1808 would be destabilized due to the steric inter-

actions between the C5±Me and the amino group.

With regard to the central torsional angles, Wiberg

et al. [31, 32] suggested that the CG and EG confor-

mations of the C±C±CyO compounds are stabilized

due to the dipole±dipole interaction between the CyO

permanent dipole and the induced dipole in the

eclipsed C±C (CG) or C±H (EG) bond. These inter-

actions explain the values of 0 and 1208 of the C±C±

CyO torsional angles. For the N±C±CyO

compounds, the torsions of the CG (08) and TG

(1808) conformations of GLY and MEG are clearly

determined by the existence of H bonding, and the

same happens in the CG forms of 2AE and 1A2PN.

3.3. Effect of solvation

Table 5 shows the relative energies in aqueous solu-

tion (Ewat) for the stable conformers previously

located in the gas phase. The electrostatic and non-

electrostatic contributions to the solvation energy are

also shown. From the comparison between Tables 1

and 5, changes in relative energies indicate that water

signi®cantly modi®es the conformational stabilities.

2MAE and 1MA2PN are especially notable, because

the most stable conformer is different in the gas phase

and in aqueous solution.

The comparison between the energy differences in

the gas phase and in solution is especially useful for

the analysis of the in¯uence of water. Thus, it can be

seen that the CG/EG differences are always reduced in

solution. There are probably two effects causing this

reduction: (a) the EG conformers are more stabilized

in solution because these forms have higher dipolar

moments (Table 4), and (b) the CG forms are


Fig. 4. Bifurcated hydrogen bonding in the CG and TG conformers of glycine (GLY)

destabilized in water, because it is known that confor-

mations presenting H bonding are less favoured in

solution. Both reasons would explain that the CG/

TG and CG/EG aqueous energy differences in the

molecules presenting the bifurcated IHB1 interaction

(2AE, 1A2PN, 4AP, 2M2AP and 3A2BN) are about

1 kcal mol21 smaller than in the gas phase. For the

rest of compounds, where only one hydrogen bond


Table 5

HF/6-31G** relative energies (in kcal mol21) in aqueous solutions (Ewat) for the stable confomers of the compounds studied. Solvation energies

(DGsol) and the electrostatic (DGel) and non-electrostatic (DGno-el) contributions are also shown

Ewat DGel DGno-el DGsol Ewat DGel DGno-el DGsol

2AE 1A2PN

CG 0.00 210.57 2.81 27.76 0.00 210.42 4.18 26.24

EG 2.02 211.76 4.33 27.43

TG 1.42 211.45 2.80 28.65

CG 0 1.12 210.95 2.59 28.36 1.25 210.62 3.89 26.73

EG 0 1.31 210.56 2.71 27.84 1.72 210.63 4.20 26.43

2MAE 2AP

CG 0.37 28.94 4.27 24.67 0.00 29.86 4.32 25.55

EG 1.90 29.27 4.30 24.98 1.26 210.44 4.36 26.08

E 0G 0.95 210.72 4.38 26.34

CG 0 0.00 29.30 3.91 25.38 0.60 210.14 4.07 26.07

EG 0 0.65 29.02 4.08 24.95 0.81 210.03 4.27 25.77

CT 0.77 210.52 4.08 26.44 1.31 210.26 4.19 26.07

E 0T 0.93 28.79 4.24 24.55 0.41 210.02 4.33 25.69

2DMAE 2M2AP

CG 0.96 27.28 5.78 21.50 0.00 29.16 6.09 23.06

EG 0.45 29.96 6.09 23.88

TG 2.12 27.61 5.78 21.83

CG 0 0.31 28.39 5.53 22.86 1.88 28.66 5.86 22.81

EG 0 0.00 27.14 5.71 21.44 0.42 29.41 6.06 23.35

2R2MAP 2S2MAP

CG 1.62 28.35 6.00 22.34 0.00 28.19 5.86 22.34

EG 2.10 28.78 6.03 22.75 1.06 28.69 5.97 22.72

CG 0 1.61 28.39 5.74 22.65 0.48 27.80 5.48 22.32

EG 0 0.21 28.36 5.81 22.55 1.45 28.70 5.79 22.91

CT 0.69 29.56 5.60 23.96 2.69 29.80 5.85 23.95

E 0T 0.00 28.30 5.85 22.44 1.45 28.18 6.02 22.16

3A2BN 1MA2PN

CG 0.00 29.92 5.98 23.94 0.36 28.64 5.70 22.94

EG 1.21 210.95 6.01 24.94 2.74 29.40 5.95 23.45

CG 0 1.15 29.74 5.59 24.15 0.00 28.83 5.28 23.55

EG 0 0.67 210.19 5.88 24.31 0.51 29.63 5.68 23.95

CT 0.80 29.96 5.71 24.25 1.19 210.44 5.49 24.96

E 0T 0.82 29.58 5.88 23.70 1.39 28.89 5.86 23.03

(IHB2 or IHB3) is present, the reduction of the energy

difference is smaller (about 0.5 kcal mol21). The same

trend is observed in the CT/ET energy differences,

which decrease about 1.5±2.0 kcal mol21, because

the CT forms are more favoured in solution due to

their higher dipole moments. This reduction is smaller

for 2AP and 3A2BN ( < 0.5 kcal mol21), probably

because their CT forms, which display H bonding,

are less stabilized for the solvent. On the other hand,

in most of the cases the CG 0/EG 0 energy differences

also decrease in solution, even though the reductions

are smaller, probably due to the similar dipolar

moments of both forms.

The energy contributions to the solvation energy

indicate that DGel is mainly responsible for the varia-

tions in relative energies, because the DGno-el energies

are similar for all the conformers of each compound.

From the values of 2AE and its monomethylated deri-

vatives, it can be concluded that the introduction of

the ®rst methyl group increases the non-electrostatic

term by about 1.4 kcal mol21. An analogous compar-

ison considering bimethylated derivatives shows that

the second methyl group increases DGno-el by about

1.8 kcal mol21. These variations are associated with

higher values of the cavitation energy, when the

methyl groups are introduced. The electrostatic

component also displays interesting trends associated

with methylation. Thus, when a methyl group is

bonded to the nitrogen, the value of DGel decreases

by 1.6 kcal mol21. If methylation takes place in the

central carbon C3, this contribution decreases by

0.7 kcal mol21. Although it is known that those

conformations with higher dipolar moments are

more stabilized by the solvent [22±24], these reduc-

tions in the electrostatic component do not seem to be

related to the total dipolar moment. The dipolar

moments of the CG conformations are similar in all

the compounds (between 1.8 and 2.4 kcal mol21, see

Table 4) and there is no clear correlation between the

values of DGel and the dipolar moments. The reduc-

tion of DGel could be related to the change of local

interactions between the solute and the solvent [33],

because the substitution of an N±H polar bond by an

N±Me group of lower polarity will reduce the stabi-

lization produced by the solvent. In a similar manner,

the substitution of C±H by C±Me also decreases the

electrostatic component, although in this case the

difference of polarity is smaller, and the same occurs

with the reduction of DGel (0.7 kcal mol21). It should

be noted, however, that methylation in R5 hardly

modi®es the value of DGel. This behaviour of the

electrostatic and non-electrostatic terms explains

why the values of DGsol decrease with methylation,

the reduction being almost additive depending on

the kind of substitution.

4. Conclusions

The conformational analysis of a series of 10 a-

aminoaldehydes and a-aminoketones presenting the

N±C±CyO unit was performed. Ab initio calcula-

tions at the Hartree±Fock level suggest that the non-

polarized 3-21G basis set is not recommended for the

study of these compounds, because the relative ener-

gies are non-systematically different to those obtained

at higher theoretical levels such as HF/6-31G** and

MP2/6-31G**. The reason for these discrepancies

could lie in the incapacity of the 3-21G basis set to

properly describe the hydrogen bonding interactions

present in these compounds. The in¯uence of electron

correlation seems to be of minor importance.

The existence of different types of intramolecular

hydrogen bonding has a large in¯uence on the confor-

mational stabilities of the N±C±CyO compounds. In

most cases, the CG forms are the most stable minima

because they can display bifurcated non-bonded inter-

actions NH2:::O. Other conformers such as CG 0 and

CT can also present ``simple'' hydrogen bonding

NH¼O, and the energy differences between confor-

mers suggest that this interaction is less intense than

the bifurcated one. On the other hand, relative ener-

gies are also in¯uenced by steric interactions between

the oxygen and nitrogen lone pairs and by the relative

orientation of methyl groups in the bimethylated

compounds. The same features permit us to explain

the observed differences, both in relative energies and

in geometries, between related N±C±CyO and C±C±

CyO compounds.

By means of the PCM method, the in¯uence of

water on the relative stabilities was estimated. This

in¯uence is related to the solute±solvent dipolar inter-

actions, to the existence of hydrogen bonding and the

degree of methylation of the molecules. The analysis

of the solvation energy components suggests that

changes in the relative energies in aqueous solution


are mainly due to the electrostatic contribution. This

term is always reduced by methylation, which could

be related to local dipolar interactions between the

solvent and different groups of the solute.

Acknowledgements

We wish to thank Professors Jacopo Tomasi and

Maurizio Cossi of the University of Pisa for the modi-

®ed version of L502 of the gaussian program used

for the PCM calculations. The authors are indebted to

the Xunta de Galicia for ®nancial support and to the

Centro de Supercomputacion de Galicia (CESGA) for

the use of computational facilities. I.P.J. wishes to

thank the Spanish Ministerio de Educacion y Ciencia

for the award of an FPI grant.

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Documents

Ab initio conformational analysis of α-aminoaldehydes and α-aminoketones in the gas phase and in aqueous solution