Metal-Mediated Addition of N-Nucleophiles to Isocyanides: Mechanistic Aspects

Abstract

Despite the long history of the investigation of nucleophilic addition to metal-bound isocyanides, some important aspects of the reaction mechanism remain unclear even for the simplest systems. In this work, the addition of the sp3-N, sp2-N, and mixed sp2/sp3-N nucleophiles (i.e., HNMe2, HN=CPh2, and H2N–N=CPh2, respectively) to isocyanides C≡NR coordinated to the platinum(II) centers in the complexes cis-[Pt(C≡NCy)(2-pyz)(dppe)]+ (2-pyz = 2-pyrazyl, dmpe = Me2PCH2CH2PMe2) and cis-[PtCl2(C≡NXyl)(C≡NMe)] was studied in detail by theoretical (DFT) methods. The mechanism of these reactions is stepwise associative rather than concerted and it includes the addition of a nucleophile to the isocyanide C atom, deprotonation of the nucleophilic moiety in the resulting intermediate, and protonation of the isocyanide N atom to give the final product. The calculated activation energy (ΔG≠) of all reactions is in the range of 19.8–22.4 kcal/mol.

Reaction between Indazole and Pd-Bound Isocyanides—A Theoretical Mechanistic Study

“…This mechanism is similar to that established previously for the reactions of amines, imines, and hydrazones to metal-bound isocyanides [ 64 ]. It starts with the formation of a van der Waals pre-reaction complex OC1 which is then transformed into intermediate INT1 via transition state TS1 upon the attack of the amino N atom at the isocyanide C atom, see Scheme 5 .…”

“…Instead, indazole reacts with 1 by the unprotonated nitrogen atom. Therefore, the mechanism of this reaction is different from that previously established for NA of amines, imines, and hydrazones to Pt-bound isocyanides [ 64 ].…”

“…This value is too high to permit the realization of Mechanism I; therefore, the nucleophilic addition of Ind by the amino N atom may be ruled out. Thus, the mechanism of the reaction of indazole with the Pd-bound isocyanides is different from that when amines, imines, and hydrazones are employed as nucleophiles [ 64 ].…”

“…The energies discussed below are Gibbs free energies G(6-311+G**) calculated as G(6-311+G**) = E(6-311+G**) – E(6-31G*) + G(6-31G*) where the basis set used is indicated. This combination of method and basis sets was tested in our previous work for NA of amines, imines, and hydrazones to metal-bound isocyanides [ 64 ] and provided excellent agreement with available experimental data [ 62 ], the DFT calculated and experimental activation enthalpies being 6.9 and 7.0 ± 0.8 kcal/mol, respectively, and the corresponding Gibbs free energies of activation being 21.6 and 19.8 ± 1.7 kcal/mol for the reaction between cis -[Pt(C≡NCy)(2-pyz)(dppe)] + and HNEt 2 .…”

“…The experimental kinetic studies [ 43 , 62 , 63 ] indicated a negative activation entropy for the reaction between amines and isocyanides ligated to the Pt(II) or Pd(II) centers. However, as recently as 2017, it was established by theoretical calculations that the mechanism of NA of amines, imines, and hydrazones (HNMe 2 , HN=CPh 2 , and H 2 N–N=CPh 2 ) to the platinum(II) complexes cis -[Pt(C≡NCy)(2-pyz)(dppe)] + (2-pyz = 2-pyrazyl, dmpe = Me 2 PCH 2 CH 2 PMe 2 ) and cis -[PtCl 2 (C≡NXyl)(C≡NMe)] is of the stepwise associative type including an attack of the nucleophile by the NH nitrogen atom at the isocyanide carbon atom followed by the amino or imino proton migration via stepwise deprotonation/protonation steps, as shown in Scheme 1 [ 64 ].…”