Synoptic Problems II. 2005

The question for this set and its answer are available as Acrobat files. Molecular models corresponding to the various systems are below. An article detailing the anticipated mechanism for this reaction (the asymmetric Strecker synthesis) is available here and reviewed here.

Models for B

In the models below, the aromatic ring substituents are not included. Structure A is coordinated on the sulfoxide oxygen by Me(OiPr)AlCN, which is formed by the reaction between Me2AlCN and iPrOH. This process attenuates the reactivity of this cyano transfer reagent, the inference being that it is made more selective.

The (monomeric) structure of the reagent is shown below, together with that of the isocyano isomer. Note particularly the unusual C-H...π double hydrogen bond that forms in each case (toggle here to see atoms: , ), helping to stabilize the structure. There is structural evidence that the "CN" group can coordinate to Al via both an N and a C in a trimeric arrangement (check this for yourself via a search of the Cambridge crystal structure database), and that either Al-NC or Al-CN coordinated monomers can result from disporportionation of this trimer.

Relative energies (kcal/mol) based on B3LYP/6-31G(d) Calculations
A, coordinated by Me(OMe)AlCN, 0.0 kcal/mol A, coordinated by Me(OMe)AlNC, +0.8 kcal/mol
tris((μ2-Cyano)-bis(bis(trimethylsilyl)methyl)-aluminium: YOYKIG

The two calculated transition states for transfer of the CN group to the imine are shown below. The (S,S)-stereoisomer is favoured over the (R,S) diastereoisomer, largely the result of the latter having an unfavourable steric interaction between the imine C-H hydrogen and the proximate face of the phenyl group. The structure of these transition states differs from that previously proposed in one important regard. The original mechanism involved a six-membered ring adopting a chair conformation, in which only the C of the CN group transferred between Al and C (TS-1 in the scheme on the left). When such a structure is subjected to calculation, it is found to rearrange such that both the C and the N of the CN group now form part of a larger 7-membered ring ( ). This ring size allows a more favourable angle of attack by the nucleophilic C of the CN at the C=N double bond. This implies that the coordinated reagent A first rearranges to the isonitrile isomer, which is only slightly higher in energy (via trimer formation and disproprtionation), and that this isonitrile is actually the active species which attacks the imine group.

TS (S,R) 1.7 kcal/mol
2.3 [ΔG 1.3] (OMe)
TS (R,R) 0.0 (barrier 18.1)
0.0 (OMe), barrier 21.3
Product, -4.5 kcal/mol

The product is formed again as an μ2-cyano bridged system, with the cyano bound to the imine carbon at the carbon, and to the Al at the nitrogen. This system, when quenched with water, results in protonation of the imino nitrogen, and displacement of the μ2-cyano from the Al by another water molecule, eventually resulting in eg Al(OH)3.

This type of alternative mechanism has previously been hinted at. Thus the guanidine catalysed Strecker reaction is thought to proceed via addition of HNC rather than HCN to methanimine: 10.1021/jo034891f.

(C) H. S. Rzepa, 19/11/05. >