Selective Generation of Aldimine and Ketimine Tautomers of the Schiff Base Condensates of Amino Acids with Imidazole Aldehydes or of Imidazole Methanamines with Pyruvates-Isomeric Control with 2- vs. 4-Substituted Imidazoles

Abstract

The Schiff base condensation of 5-methyl-4-imidazole carboxaldehyde, 5Me4ImCHO, and the anion of an amino acid, H₂N-CH(R)CO₂^- (R = -CH₃, -CH(CH₃)₂ and -CH₂CH(CH₃)₂), gives the aldimine tautomer, Im-CH=N-CH(R)CO₂^-, while that of 5-methylimidazole-4-methanamine, 5MeIm-4-CH₂NH₂, with a 2-oxocarboxylate anion, R-C(O)-CO₂^-, gives the isomeric ketimine tautomer, Im-CH₂-N=C(R)CO₂^-. All are isolated as the neutral nickel(II) complexes, NiL₂, and are characterized by single crystal structure determination, IR, and positive ion ESI MS. In the cases of the 4 substituted imidazoles, either 5MeIm-4-CHO or 5MeIm-4-CH₂NH₂, both the aldimine and ketimine complexes are isolated cleanly with no evidence of an equilibrium between the two tautomers under the experimental conditions. The aldimines are blue while the tautomeric ketimines are green. In contrast, for the 2-substituted imidazoles, with either Im-2-CHO or Im-2-CH₂NH₂, the isolated product from the Schiff base condensation is the ketimine, which in the solid is green, as observed for the 4-isomer. These results suggest that for the 2-substituted imidazoles, there is a facile equilibrium between the aldimine and ketimine tautomers, and that the ketimine form is the thermodynamically favored tautomer. The aldimine tautomers of the 4-substituted imidazoles have three stereogenic centers, the nickel (Δ or Ʌ) and the two alpha carbon atoms (R or S). The observed pair of enantiomers is the ɅRR/ΔSS enantiomeric pair, suggesting that this pair is lower in energy than the others and that this is in general the preferred chiral correlation in these complexes.

Keywords: Schiff base; aldimine; amino acids; homochirality; imidazole; ketimine; pyruvates; tautomerization.

Figure 1

Two types of tautomerism observed in Schiff bases.

Figure 2

The proposed steps in the racemization of an AA. Deprotonation of the chiral aldimine at C_α followed by tautomerization gives an achiral ketimine. Reprotonation of the ketimine gives an aldimine, which has a stereogenic center at C_α but is now racemic.

Figure 3

The twelve reactions discussed in this study. Method (a), top, is the reaction of an imidazole carboxaldhyde with the anion of an amino acid to produce an aldimine complex, if there is no tautomerization. Method (b), bottom, is the reaction of a methanamine imidazole with a pyruvate to produce a ketimine complex, if there is no tautomerization. Reactions on the left are of a 2-substituted imidazole (carboxaldehyde or methanamine), while those on the right are of a 4-substituted imidazole (carboxaldehyde or methanamine). For the reactions on the left, R’ = H and R = Me, or R’ = Me and R = Me, or i-Butyl; while for those on the right, R = Me, i-propyl or i-butyl. The reaction conditions for all method (a) reactions are thirty minutes in refluxing methanol. For method (b), the reflux times are extended to three to ten hours. Full details for all reactions are given in Section 3.4.

Figure 4

Line drawings giving the abbreviations used for both the aldehydes on the left and the methanamines on the right. In terms of the Schiff base condensations, the aldehydes on left are equivalent to the methanamines on the right when condensed by method (a) and method (b), respectively (Figure 3). In a similar fashion, the amino acid anions of, A, V and L are synthetically equivalent to sodium salts of pyruvic(A), 3-methyl-2-oxobutyric(V) or 4-methyl-2-oxovaleric(L) acid.

Figure 5

Line drawings illustrating that the difference between Ni(V_Ald-5Me4Im)₂ and Ni(V_Ket-5Me4Im)₂ is the location of the imine bond. For the aldimine (left) the imine bond is between the nitrogen atom of the amino acid, N_AA, and aldehyde carbon atom, C_ald, while for the ketimine (right) it is between N_AA and alpha carbon atom of the amino acid, C_α.

Figure 6

Overlay of structural diagrams of the triclinic Ni(A_ket-NMe2Im)₂ trihydrate produced by method (a) and monoclinic Ni(A_ket-NMe2Im)₂ dihydrate produced by method (b) illustrating the overall similarity. The overlayed atoms for each complex are the Ni(II) and its six donor atoms. RMS is 0.0799. The colors designate the type of atom, Ni (green), C (gray), N (blue), O (red) and H (yellow).

Figure 7

Structure of Ni(L_Ald-5Me4Im)₂, which is representative of Ni(A_Ald-5Me4Im)₂, Ni(A_Ket-5Me4Im)₂, Ni(V_Ald-5Me4Im)₂, Ni(V_Ket-5Me4Im)₂ and Ni(L_Ket-5Me4Im)₂, ignoring the location of the imine bond and the alkyl substituents. The colors designate the type of atom, Ni (green), C (gray), N (blue), O (red) and H (yellow).

Figure 8

Line drawing illustrating the connectivity in the aldimine and ketimine tautomers of the Schiff bases prepared from 5Me4Im by methods (a) and (b). The difference between the tautomers is the location of the imine bond. The double bond for the aldimine is between N_AA and C_ald, and for the ketimine it is between N_AA and C_α. The ligands bind to the nickel(II) ion through the N_Im, N_AA and O atoms.

Figure 9

The overlay of the Ni(A_Ald-5Me4Im)₂ and Ni(A_Ket-5Me4Im)₂ structures depicting both the overall similarities and the significant differences at C_ald and C_α. The overlayed atoms are the Ni(II) and its six donor atoms of each complex. RMS = 0.0571. Note C_ald and C_α. (lower left and upper right). The lone H atom on the C_ald of the aldimine form bisects the geminal H atoms of the ketimine form, and the Me group on the C_α of the ketimine form bisects the H atom and the Me group on the same atom of the aldimine form. The colors designate the type of atom, Ni (green), C (gray), N (blue), O (red) and H (yellow).

Figure 10

The three resonance structures of the deprotonated aldimine complex of a 2-substituted imidazole (I–III top, R’ is H or Me) and 5Me4Im (I’–III’ bottom). There is a significant stability difference between III and III’, which provides an explanation for the observed isomeric difference in reactivity between 2- and 4-substituted imidazoles.

Figure 11

Illustration of the forms of the Λ and Δ aldimine complexes discussed here.

Figure 12

The supramolecular structure of Ni(L_Ald-5Me4Im)₂. Hydrogen atoms are omitted for clarity. All complexes of this grid are Λ and all the C_α‘s are R. Ni(L_Ket-5Me4Im)₂ Ni(V_Ald-5Me4Im)₂ also exhibit homochiral grids. Ni(V_Ket-5Me4Im)₂ gives an achiral grid. The hydrogen bond that holds this together is the N-H ^…. O (non-nickel bound carboxylate). The N ^…. O distances are as follows: Ni(V_Ald-5Me4Im)₂: 2.629(8), 2.646(9), 2.638(10) and 2.619(9) Å, Ni(V_Ket-5Me4Im)₂: 3.0735(19) and 3.023(2) Å. The hydrogen bond in this case is to both carboxylate O atoms, Ni(L_Ald-5Me4Im)₂: 2.617(4) Å and Ni(L_Ket-5Me4Im)₂: 2.676 Å. The colors designate the type of atom, Ni (green), C (gray), N (blue) and O (red).

Figure 13

Photographs of the blue Aldimine, Ni(A_Ald-5Me4Im)₂ (left), and green Ketimine, Ni(A_Ket-5Me4Im)₂ (right). The photograph underscores that a significant difference in color may be due to small differences in λ_MAX, 905 and 579 nm vs. 937 and 594 nm. All the aldimine and ketimine complexes of 5Me4Im are blue and green, respectively, with no evidence of tautomerization.