Mechanistic Study of the Mechanochemical Pd^II-Catalyzed Bromination of Aromatic C–H Bonds by Experimental and Computational Methods

Abstract

The mechanism of mechanochemical Pd II -catalyzed selective bromination of the carbon−hydrogen bond in azobenzene by N-bromosuccinimide (NBS) was investigated using in situ timeresolved Raman spectroscopy and quantum-chemical (density functional theory, DFT) calculations. Raman monitoring of the reactions in the presence of different amounts of Pd(OAc) 2 , ptoluenesulfonic acid (TsOH), and acetonitrile (MeCN) as solid and liquid additives provided direct evidence that the formation of the carbon−halogen bond in the solid state proceeds from catalytically active cyclopalladated intermediates that are monomeric in the presence of MeCN or dimeric without MeCN. The reaction pathway via the monomeric palladacycle is more efficient than the pathway via the dimeric palladacycle for the bromination of azobenzene, offering better yields and faster reactions. Both reaction routes require the presence of TsOH, which is involved in the formation of the active Pd II catalysts and palladacyclic intermediates, as well as in the activation of NBS. Four possible reaction mechanisms for the bromination of cyclopalladated azobenzene were investigated by DFT modeling. Three mechanistic pathways include (i) oxidative addition of the Br to Pd atom and (ii) reductive elimination by the 1,2-displacement of Br to the carbon atom. In one pathway, the transfer of Br to Pd occurs only after the initial displacement of the neutral ligand by NBS. In another, the Pd atom is inserted directly into the N−Br bond of NBS, and in the last one, Br + migrates spontaneously from the protonated NBS to Pd. In all three cases, the subsequent elimination step is remarkably lower in energy. In the fourth mechanism, Br + migrates from free NBS directly to the activated carbon, simultaneously with the Pd−C bond breaking. Besides NBS, the hydrogen bond complex NBS•••TsOH was also considered as the bromine source. None of the considered mechanisms can be definitely rejected on the basis of experimental findings and the current modeling level, and more than one could be operative depending on the reaction conditions.

Mechanochemical halogenation of unsymmetrically substituted azobenzenes

“…In situ Raman monitoring of C–H bond activation was possible for L6 and L7 , while in the case of L8 , fluorescence prevented a more detailed insight into this reaction. The monitoring results confirmed the complete conversion of azobenzenes L6 and L7 to their monopalladated products after about one hour of milling, as well as a reaction course similar to that of the analogous reaction of L1 [ 51 ] ( Figure 5b and Figure S28 in Supporting Information File 1 ).…”

“…The results of in situ and ex situ spectroscopic monitoring along with the structural characterization of the intermediates have shown that the mechanism of the halogenation of azobenzenes with electron-accepting substituents is consistent with the proposed mechanistic schemes for the bromination of the unsubstituted azobenzene L1 [ 51 ]. Thus, the halogenation of L6 – 8 begins with the formation of the catalytically active Pd II species, Pd(OTs) 2 (MeCN) 2 , from Pd(OAc) 2 , TsOH, and MeCN.…”

“…In contrast to the reactions of L1 [ 51 ], the halogenation of azobenzene substrates containing strong electron-donating substituents (4-methoxyazobenzene ( L2 ), 4-aminoazobenzene ( L3 ), 4-dimethylaminoazobenzene ( L4 ), and 4-(dimethylamino)-4'-nitroazobenzene ( L5 )) with NXS (X = Cl and Br) occurred in the absence of the added Pd II catalyst and additives. These reactions in most cases produced electrophilic substitution products that were halogenated in the ortho position(s) relative to the electron-donating substituent ( Scheme 1 and Table 1 ), as confirmed by Raman (Figures S14–S22 in Supporting Information File 1 ) and NMR spectroscopy (Figures S40–S76 in Supporting Information File 1 ).…”

“…Since the complex Pd(OTs) 2 (MeCN) 2 was identified as the active catalyst, formed in situ, in the bromination reaction of Scheme 2: Pd II -catalyzed halogenation of azobenzene and its para-halogenated derivatives. L1 [51], the analogous reactions of L6-8 were carried out using Pd(OTs) 2 (MeCN) 2 as the catalyst instead of Pd(OAc) 2 . As expected, the yields of LnBr-IV products were comparable to those obtained in the reactions with the Pd(OAc) 2 precatalyst.…”

“…Only recently, our group carried out a detailed synthetic and mechanistic study of the mechanochemical Pd II -catalyzed bromination of unsubstituted azobenzene ( L1 ) by N -bromosuccinimide (NBS) under neat grinding (NG) and liquid-assisted grinding (LAG) conditions in a ball mill [ 51 ]. Insight into the dynamics of the formation of reaction intermediates and products was obtained by in situ Raman monitoring that provided information on the nature of the catalytically active Pd II species, cyclopalladated intermediates, and products ( Figure 1 ).…”