A computational study of the Hofmann elimination pathway for the Morita-Baylis-Hillman reaction under DABCO catalysis. Participation of a bridge-head ylide
In comparison to the popular pathway involving proton-transfer via a four-centred cyclic transition state structure, the recently proposed overall lower energy pathway involving protontransfer via a seven-centred cyclic transition state structure followed by Hofmann elimination for the Me3N-catalyzed Morita-Baylis-Hillman reaction is applicable to the DABCO-catalyzed reaction equally well. This finding clearly establishes that the zwitterion at the bridge-head in DABCO is well tolerated. Also, the activation free energy of the rate-limiting aldol reaction under DABCO-catalysis is lower than that under Me3N-catalysis, suggesting that DABCO is likely a better catalyst to achieve faster conversion.Introduction. The Morita-Baylis-Hillman (MBH) reaction, Scheme 1, is a broad range, synthetically useful chemical transformation allowing the construction of a myriad of densely functionalized methylene--hydroxy derivatives. 1,2 The reaction involves coupling of an electrophile, such as an aldehyde, with an activated alkene (normally with an electron-withdrawing group) in the presence of a Lewis base catalyst such as Me3N, DABCO and DBU. Based on its atom economy and feasibility, the MBH reaction is regarded as one of the most efficient transformations in organic chemistry. 3 According to the generally accepted mechanism, the aldol product 5 undergoes a proton-transfer reaction by the way of a four-centred cyclic transition state (TS) structure, as shown, to form the 1,3-zwitterion 6a, which falls through E1cB elimination, as shown, to the MBH product 7 and also regenerate the Lewis base to allow it re-enter the reaction cycle. The reaction, therefore, is catalytic in the Lewis base.Scheme 1. The generally accepted pathway for the Me3N-catalyzed MBH reaction of cyclopentenone with acetaldehyde
<!>Scheme 2. The proposed reaction pathway for the MBH reaction of cyclopentenone and acetaldehyde catalyzed by trimethylamine<!>Conclusion.<!>Supporting Information<!>ORCID
<p>We have carried out a computational study of the Me3N-catalyzed MBH reaction and recently reported an alternate overall lower energy pathway. 4 This pathway involved proton-transfer in the aldol product through a seven-centred cyclic transition state structure, followed by Hofmann elimination to form the observed product and also regenerate the catalyst as shown in Scheme 2. TS1, TS2, TS3 and TS4 represent, respectively, the transition states for conjugate addition of Me3N to cyclopentenone to form an enolate 3, aldol reaction of the enolate with acetaldehyde to form the oxyanion 5, proton-transfer from one of the methyl groups on N to the oxyanion to form 6b and Hofmann elimination to generate the MBH product 7. The energy required to achieve TS2 was merely 2.6 kcal/mol and, likewise, the activation energy for the Hofmann elimination, 9.3 kcal/mol, was significantly lower than that for the proton-transfer through four-centred cyclic TS structure, 24.2 kcal/mol, which is accompanied immediately with E1cB elimination.</p><!><p>Having shared the finding with a good colleague, 5 concern was raised as to whether the same was permissible with DABCO (1,4-diazabicyclo[2.2.2]octane) also because it would have to generate a bridge-head zwitterion. A truly genuine concern as it was, we felt wanted to investigate a parallel of the Me3N-catalyzed reaction by using DABCO as the catalyst.</p><p>Computational methods. All the structures, geometry optimizations and TS structure searches were carried out using the global hybrid meta-GGA M06-2X density functional and 6-311++G(d,p) basis set at 298.15 K. 6 The optimized structures were verified as minima or first order saddle points on their potential energy surfaces by harmonic vibrational frequency analysis. Calculations were carried out using the Gaussian 16 suite of programs. 7</p><p>Results and Discussion. We approached the problem by first studying the simpler DABCO, N-methyl-DABCO and the ylide formed from deprotonation at the position adjacent to the bridge-head. The computed structures of the two species are given in Figure 1. The difference in the structures is in the shape of the ring which is a clear boat in DABCO and N-methyl-DABCO, and twist-boat in the ylide.</p><p>The survival of the bride-head ylide as a stable structure instilled confidence in us to proceed and estimate the entire reaction profile of the MBH reaction of cyclopentenone with acetaldehyde catalyzed by DABCO. The reaction profile of the DABCO-catalyzed reaction is given in Figure 2. This profile is much similar to the Me3N-catalyzed reaction in every respect. In particular, the activation free energy for (a) the proton-transfer through seven-centred cyclic TS structure is 2.4 kcal/mol against the 2.6 kcal/mol under Me3N-catalysis, (b) the Hofmann elimination is 11.2 kcal/mol against the 9.3 kcal/mol under Me3N-catalysis, (c) the aldol reaction is 39.8 kcal/mol against the 41.9 kcal/mol under Me3N-catalysis, (d) the conjugate addition is 27.7 kcal/mol against the 29.6 kcal/mol under Me3N-catalysis, and (e) the proton-transfer through four-centred cyclic TS structure, as in the conventional mechanism, is 25.0 kcal/mol against the 24.2 kcal/mol under Me3N-catalysis. The aldol reaction continues to be the rate-limiting reaction in the entire sequence. However, a remarkable feature to note in here is the lower activation free energy of the DABCO-catalyzed aldol reaction than the Me3N-catalyzed reaction by 2.1 kcal/mol. The DABCO-catalysis is, therefore, expected to result in a faster reaction than Me3N-catalysis.</p><p>We have calculated the deuterium isotope effects, KH/KD, for the conventional route involving protontransfer through a four-centred cyclic transition state structure and the present Hofmann elimination route and found it to be 1.36 in each instance. Several MBH reactions under solvent-less conditions have been reported in the literature and often found to be faster and superior yielding than the reactions in solvents. 8</p><!><p>The DABCO-catalysis of MBH reaction parallels the catalysis by Me3N and the perceived difficulty of generating a bridge-head zwitterion is just not there as anticipated from the preliminary investigations on the structural aspects of N-methyl-DABCO and the consequent bridge-head ylide.</p><p>The DABCO-catalyzed Hofmann elimination pathway for the MBH reaction is also lower in energy than the conventional pathway requiring proton-transfer through a four-centred cyclic TS structure to form a species ready for E1cB elimination. Also, for lowering the activation free energy of the rate-limiting aldol reaction by 2.1 kcal/mol, DABCO is expected to result in a faster reaction than Me3N.</p><p>The study of the influence of solvents 9 on the overall reaction profile and the associated kinetic isotope effect kH/kD is under investigation.</p><!><p>Supporting Information (SI) available: Cartesian coordinates of the optimized substrates, transition state structures, Gibbs' free energies of the ground and transition state structure studied at the level M06-2X/6-311++G(d,p).</p><!><p>Veejendra K. Yadav: 0000-0001-8294-0677</p>