Trifunctional Metal Ion-Catalyzed Solvolysis: Cu(II)-Promoted Methanolysis of N,N-bis(2-picolyl) Benzamides Involves Unusual Lewis Acid Activation of Substrate, Delivery of Coordinated Nucleophile, Powerful Assistance of the Leaving Group Departure

Abstract

The methanolyses of Cu(II) complexes of a series of N,N-bis(2-picolyl) benzamides (4a-g) bearing substituents X on the aromatic ring were studied under (s)(s)pH-controlled conditions at 25 °C. The active form of the complexes at neutral (s)(s)pH has a stoichiometry of 4:Cu(II):((-)OCH(3))(HOCH(3)) and decomposes unimolecularly with a rate constant k(x). A Hammett plot of log(k(x)) vs σ(x) values has a ρ(x) of 0.80 ± 0.05. Solvent deuterium kinetic isotope effects of 1.12 and 1.20 were determined for decomposition of the 4-nitro and 4-methoxy derivatives, 4b:Cu(II):((-)OCH(3))(HOCH(3)) and 4g:Cu(II):((-)OCH(3))(HOCH(3)), in the plateau region of the (s)(s)pH/log(k(x)) profiles in both CH(3)OH and CH(3)OD. Activation parameters for decomposition of these complexes are ΔH(++) = 19.1 and 21.3 kcal mol(-1) respectively and ΔS(++) = -5.1 and -2 cal K(-1) mol(-1). Density functional theory (DFT) calculations for the reactions of the Cu(II):((-)OCH(3))(HOCH(3)) complexes of 4a,b and g (4a, X = 3,5-dinitro) were conducted to probe the relative transition state energies and geometries of the different states. The experimental and computational data support a mechanism where the metal ion is coordinated to the N,N-bis(2-picolyl) amide unit and positioned so that it permits delivery of a coordinated Cu(II):((-)OCH(3)) nucleophile to the C═O in the rate-limiting transition state (TS) of the reaction. This proceeds to a tetrahedral intermediate INT, occupying a shallow minimum on the free energy surface with the Cu(II) coordinated to both the methoxide and the amidic N. Breakdown of INT is a virtually barrierless process, involving a Cu(II)-assisted departure of the bis(2-picolyl)amide anion. The analysis of the data points to a trifunctional role for the metal ion in the solvolysis mechanism where it activates intramolecular nucleophilic attack on the C═O group by coordination to an amidic N in the first step of the reaction and subsequently assists leaving group departure in the second step. The catalysis is very large; compared with the second order rate constant for methoxide attack on 4b, the computed reaction of CH3O(-) and 4b:Cu(II):(HOCH(3))(2) is accelerated by roughly 2.0 × 10(16) times.

Unusual metal complexes of N,N-bis(2-picolyl)amides – A comparative study of structure and reactivity

“…Further studies support this reaction mechanism. [13,14] Within the last 5 years, our group succeeded in demonstrating the synthetic value of N,N-bis (2-picolyl)amides and widened the scope on similar chelating amides. The possibility to cleave them in a mild and selective manner makes them suitable for applications as linker molecules in solid-phase-chemistry or as protecting groups for carboxylic M A N U S C R I P T…”

“…13 C NMR spectrum of NaphBPA (1). UV-VIS-spectra of [(NaphBPA)CuCl 2 ], [(NaphBPA)CuBr 2 ], [(NaphBPA)Cu(OTf)(OH 2 ) 2 ](OTf) (in MeCN).…”

Bio-inspired approaches to accelerating metal ion-promoted reactions: enzyme-like rates for metal ion mediated phosphoryl and acyl transfer processes

“…pK values of ≤ 6.5 [52,53]. The Hammett plot of the lg(k max ) vs. σ x value of the substituents on 15 has a gradient of 0.80 ± 0.05 [52] showing that there is some negative charge building up on the aryl group in the rate limiting TS. Since the plot is linear over the entire group, there is no evidence for a change in mechanism or rate limiting step in passing from substrates having electron donors to those having withdrawing substituents.…”

“…The implications and additional demonstrations of this discovery remained relatively dormant until much later when physical studies of such M(II):amides [45][46][47] and the demonstration of their synthetic utility [48] appeared. These, as well as reports on the methanolysis of metal complexes of secondary amides [49,50] prompted us to investigate the mechanism of metal ion promoted alcoholysis under s s pH controlled conditions [51][52][53]. pK values of ≤ 6.5 [52,53].…”

“…These, as well as reports on the methanolysis of metal complexes of secondary amides [49,50] prompted us to investigate the mechanism of metal ion promoted alcoholysis under s s pH controlled conditions [51][52][53]. pK values of ≤ 6.5 [52,53]. The Hammett plot of the lg(k max ) vs. σ x value of the substituents on 15 has a gradient of 0.80 ± 0.05 [52] showing that there is some negative charge building up on the aryl group in the rate limiting TS.…”