Wrong tertiary amide conformation

Dear all,

The 3D optimization of several tertiary amides with Marvin Sketch 3.2.0 led to the following observation : the carbon from the CO is hybridized sp2, the nitrogen is hybridized sp2 and the planes of these two sp2 are orthogonal. It can be found in litterature that bulky tertiary amides are not coplanar and often somehow orthogonal (N,N-dialkyl amides). The problem is that in that last case, there is absolutely no justification for the nitrogen to be sp2 hybridized. The sp2-sp2 hybridization at the amide bond can only be justified when amide is coplanar and delocalization can take place all throughout the amide function. With 90° angles, there is no possible delocalization with the nitrogen and it can no more be sp2 (trigonal) but rather sp3 (pyramidal).

In absence of justification for this orthogonal sp2-sp2 orientation, this output from the 3D optimization is false and gives bad 3D structures. Can you please confirm there is a problem and explain how/when it will be solved ?

  References :

Lewin et al., Tetrahedron 1975, Vol31 pp207-215 : Restricted Rotation in Amides - VI : "for tertiary amides it is observed that the barrier to rotation decreases with the bulk of substituents" ; "at least two mechanisms are effective in determining the non-planarity of the amide group : torsion around the C'-N bond and the non planar hybridization of the nitrogen" ; "the non-planar hybridization of the nitrogen, [...] seems to have a greater weight when larger deviations from planarity are required" ; "although the equilibrium conformation of the amide group may be planar or close to it, out of plane deformation can evidently be made at very low energy cost"

 The Amide Linkage: Structural Significance in Chemistry, Biochemistry, and Materials Science by Arthur Greenberg, Curt M. Breneman, Joel F. Liebman / Wiley-IEEE, 2002 see p58

 Brameld et al., J.Chem.Inf.Model. 2008, 48, 1-24 : Small Molecule Conformational Preferences Derived from Crystal Structure Data. A Medicinal Chemistry Focused Analysis. p8 : "of more than 7500 amides, only 144 strongly sterically hindered amides have torsions angles between 40 and 140°"

Niklas et al., Dalton Trans., 2006, 3188-3199 : The chemistry of nitrogen coordinated teriary carboxamides. Description of several examples of non planar tertiary amides (involved in a metal complex) in which the nitrogen is pyramidal ; p3189 : "A characteristic feature of all complexes is a non-planar amide group with a significantly pyramidal nitrogen atom. This is expected because sigma-donation of the N-lone pair lifts the amide resonance and requires a transition from sp2 to sp3 hybridisation."

Thanks in advance

Best Regards

Dear Jean-Claude Amaral, thank you for reporting inaccureate geometries around amide bond and also for the useful ferences. Our 3D structure generator uses the in house patched otherwise simple Dreiding forcefield. The issue you ponted out requires either further refinement of the parameters of this FF or the implementation one or more new ones. The implementation of the more sophisticated MMFF is on the way. The refined Dreiding FF or MMFF is planned after 5.3. Regards, Adrian   jamaral wrote:

Dear all, The 3D optimization of several tertiary amides with Marvin Sketch 3.2.0 led to the following observation : the carbon from the CO is hybridized sp2, the nitrogen is hybridized sp2 and the planes of these two sp2 are orthogonal. It can be found in litterature that bulky tertiary amides are not coplanar and often somehow orthogonal (N,N-dialkyl amides). The problem is that in that last case, there is absolutely no justification for the nitrogen to be sp2 hybridized. The sp2-sp2 hybridization at the amide bond can only be justified when amide is coplanar and delocalization can take place all throughout the amide function. With 90° angles, there is no possible delocalization with the nitrogen and it can no more be sp2 (trigonal) but rather sp3 (pyramidal). In absence of justification for this orthogonal sp2-sp2 orientation, this output from the 3D optimization is false and gives bad 3D structures. Can you please confirm there is a problem and explain how/when it will be solved ?   References : Lewin et al., Tetrahedron 1975, Vol31 pp207-215 : Restricted Rotation in Amides - VI : "for tertiary amides it is observed that the barrier to rotation decreases with the bulk of substituents" ; "at least two mechanisms are effective in determining the non-planarity of the amide group : torsion around the C'-N bond and the non planar hybridization of the nitrogen" ; "the non-planar hybridization of the nitrogen, [...] seems to have a greater weight when larger deviations from planarity are required" ; "although the equilibrium conformation of the amide group may be planar or close to it, out of plane deformation can evidently be made at very low energy cost"  The Amide Linkage: Structural Significance in Chemistry, Biochemistry, and Materials Science by Arthur Greenberg, Curt M. Breneman, Joel F. Liebman / Wiley-IEEE, 2002 see p58  Brameld et al., J.Chem.Inf.Model. 2008, 48, 1-24 : Small Molecule Conformational Preferences Derived from Crystal Structure Data. A Medicinal Chemistry Focused Analysis. p8 : "of more than 7500 amides, only 144 strongly sterically hindered amides have torsions angles between 40 and 140°" Niklas et al., Dalton Trans., 2006, 3188-3199 : The chemistry of nitrogen coordinated teriary carboxamides. Description of several examples of non planar tertiary amides (involved in a metal complex) in which the nitrogen is pyramidal ; p3189 : "A characteristic feature of all complexes is a non-planar amide group with a significantly pyramidal nitrogen atom. This is expected because sigma-donation of the N-lone pair lifts the amide resonance and requires a transition from sp2 to sp3 hybridisation." Thanks in advance Best Regards

 

Jean-Claude Amaral,

because of the frequent occurance of the tertiary amide substrucure I am starting to solve this issue promptly. I will let you know here when fixed.

Regards,

Adrian

 

Dear Jean-Claude Amaral,

The planarity issue together with plenty other structural improvements is solved and will be avilable in marvin 5.3.

Thank you for the bug report.

Regards,

Adrian