Analyzing site selectivity in Rh2(esp)2-catalyzed intermolecular C-H amination reactions

Abstract

Predicting site selectivity in C-H bond oxidation reactions involving heteroatom transfer is challenged by the small energetic differences between disparate bond types and the subtle interplay of steric and electronic effects that influence reactivity. Herein, the factors governing selective Rh2(esp)2-catalyzed C-H amination of isoamylbenzene derivatives are investigated, where modification to both the nitrogen source, a sulfamate ester, and substrate are shown to impact isomeric product ratios. Linear regression mathematical modeling is used to define a relationship that equates both IR stretching parameters and Hammett σ(+) values to the differential free energy of benzylic versus tertiary C-H amination. This model has informed the development of a novel sulfamate ester, which affords the highest benzylic-to-tertiary site selectivity (9.5:1) observed for this system.

Figure 1

(a) Rh₂(esp)₂-catalyzed C–H amination of isoamylbenzene, demonstrating the sensitivity of site selection to the sulfamate ester nitrene source. (b) Proposed mechanism for the amination reaction.

Figure 2

Twenty-membered sulfamate ester library used to probe the reaction’s site-selection sensitivity. Ratios, determined by GC analysis, are averaged over three experimental runs. Bolded and asterisked sulfamate ester structures represent the DoE-defined subset of nitrene sources.

Figure 3

Schematics of the Sterimol parameter system, describing the subparameters B₁ (minimum radius), B₅ (maximum radius), and L (length). Comparisons of nPr and CH₂t-Bu demonstrate a deficiency in the Sterimol parameters, where sterically distinct groups are similarly described.

Figure 4

Computationally derived IR spectrum for sulfamate ester 2a, MeOSO₂NH₂. Vibrations used as modeling parameters are color-coded, and graphical depictions approximating vibrational motions are presented. Vibrational frequency and intensity ranges for the 20-membered sulfamate ester library are presented.

Figure 5

Plot of measured ΔΔG^‡ versus Hammett σ⁺ for the DoE set of sulfamate esters evaluated in the isoamylbenzene substrate series R′ = OMe (1a), t-Bu (1c), H (1), Br (1d), CF₃ (1b). ΔΔG^‡ = −RT ln(tertiary/benzylic), where T is 23 °C. Omitted from this plot are data points corresponding to R = CH₂CCl₃, R′ = OMe (benzylic-to-tertiary ratio >100:1) and R = CH(CH₂Cl)₂, R′ = Br (no measurable products observed).

Figure 6

(a) Normalized mathematical relationship, derived from tabulated training set in Table 1, describing differential free energy of benzylic (B)-to-tertiary (T) amination. R: ideal gas constant, T: 23 °C. (b) Predicted versus measured ΔΔG^‡ plot of training set and external validations. Grayed data point, designated as an outlier, represents R = CH(CF₃)₂, R′ = H. (c) Leave-one-out (LOO) analysis.

Figure 7

(a) Representation of increasing C–O stretch frequency (ν_CO) versus sulfamate ester R group. (b) Representation of increasing intensity of O–S–N asymmetric stretch (I_OSN) versus sulfamate ester R group. Grayed columns highlight model-informed predictions 2u (R = CH₂CF₂CF₃) and 2v (R = CH₂(CF₂)₂CF₃).

Figure 8

(a) Plot of predicted versus measured ΔΔG^‡ for amination of isoamylbenzene, 1. A mathematical model correlating differential reaction free energy (ΔΔG^‡) with IR vibrational data and Hammett σ⁺ parameters informed the design of new sulfamate esters. Sulfamate ester 2u affords the highest B:T selectivity reported, to date, for Rh-catalyzed amination of isoamylbenzene. (b) Preparative scale (0.5 mmol) reactions using sulfamate ester 2u.