Intermolecular Insertion of an N,N-Heterocyclic Carbene into a Nonacidic CH Bond: Kinetics, Mechanism and Catalysis by (K-HMDS)2 (HMDS=Hexamethyldisilazide)

• Published in: Chemistry : a European journal Vol. 12; no. 20; pp. 5361 - 5375
• Main Authors: Lloyd-Jones, Guy C., Alder, Roger W., Owen-Smith, Gareth J. J.
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag 05.07.2006; WILEY‐VCH Verlag
• Subjects: carbenes; homogeneous catalysis; isotope effects; kinetics; potassium
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.200600266

The reaction of 2‐[13C]‐1‐ethyl‐3‐isopropyl‐3,4,5,6‐tetrahydropyrimidin‐1‐ium hexafluorophosphate ([13C1]‐1‐PF6) with a slight excess (1.03 equiv) of dimeric potassium hexamethyldisilazide (“(K‐HMDS)2”) in toluene generates 2‐[13C]‐3‐ethyl‐1‐isopropyl‐3,4,5,6‐tetrahydropyrimid‐2‐ylidene ([13C1]‐2). The hindered meta‐stable N,N‐heterocyclic carbene [13C1]‐2 thus generated undergoes a slow but quantitative reaction with toluene (the solvent) to generate the aminal 2‐[13C]‐2‐benzyl‐3‐ethyl‐1‐isopropylhexahydropyrimidine ([13C1]‐14) through formal CH insertion of C(2) (the “carbene carbon”) at the toluene methyl group. Despite a significant pKa mismatch (ΔpKa 1+ and toluene estimated to be ca. 16 in DMSO) the reaction shows all the characteristics of a deprotonation mechanism, the reaction rate being strongly dependent on the toluene para substituent (ρ=4.8(±0.3)), and displaying substantial and rate‐limiting primary (kH/kD=4.2(±0.6)) and secondary (kH/kD=1.18(±0.08)) kinetic isotope effects on the deuteration of the toluene methyl group. The reaction is catalysed by K‐HMDS, but proceeds without cross over between toluene methyl protons and does not involve an HMDS anion acting as base to generate a benzyl anion. Detailed analysis of the reaction kinetics/kinetic isotope effects demonstrates that a pseudo‐first‐order decay in 2 arises from a first‐order dependence on 2, a first‐order dependence on toluene (in large excess) and, in the catalytic manifold, a complex noninteger dependence on the K‐HMDS dimer. The rate is not satisfactorily predicted by equations based on the Brønsted salt‐effect catalysis law. However, the rate can be satisfactorily predicted by a mole‐fraction‐weighted net rate constant: −d[2]/dt=({x2 kuncat}+{(1−x2) kcat})[2]1[toluene]1, in which x2 is determined by a standard bimolecular complexation equilibrium term. The association constant (Ka) for rapid equilibrium–complexation of 2 with (K‐HMDS)2 to form [2(K‐HMDS)2] is extracted by nonlinear regression of the 13C NMR shift of C(2) in [13C1]‐2 versus [(K‐HMDS)2] yielding: Ka=62(±7) M−1; δC(2) in 2=237.0 ppm; δC(2) in [2(K‐HMDS)2]=226.8 ppm. It is thus concluded that there is discrete, albeit inefficient, molecular catalysis through the 1:1 carbene/(K‐HMDS)2 complex [2(K‐HMDS)2], which is found to react with toluene more rapidly than free 2 by a factor of 3.4 (=kcat/kuncat). The greater reactivity of the complex [2(K‐HMDS)2] over the free carbene (2) may arise from local Brønsted salt‐effect catalysis by the (K‐HMDS)2 liberated in the solvent cage upon reaction with toluene. (K‐HMDS)2 is an activator not a protector of the N,N‐heterocyclic carbene, 3‐ethyl‐1‐isopropyl‐3,4,5,6‐tetrahydropyrimid‐2‐ylidene towards formal CH insertion into the toluene methyl group. This is the contra‐intuitive conclusion derived from kinetic, thermodynamic and isotopic labelling studies, which demonstrate that the reaction proceeds via a toluene deprotonation mechanism (see scheme).