Deciphering the Microdroplet Acceleration Factors of Aza-Michael Addition Reactions

Microdroplet chemistry is emerging as a great tool for
accelerating
reactions by several orders of magnitude. Several unique properties
such as extreme pHs, interfacial electric fields (IEFs), and partial
solvation have been reported to be responsible for the acceleration;
however, which factor plays the key role remains elusive. Here, we
performed quantum chemical calculations to explore the underlying
mechanisms of an aza-Michael addition reaction between methylamine
and acrylamide. We showed that the acceleration in methanol microdroplets
results from the cumulative effects of several factors. The acidic
surface of the microdroplet plays a dominating role, leading to a
decrease of ∼9 kcal/mol in the activation barrier. We speculated
that the dissociation of both methanol and trace water contributes
to the surface acidity. An IEF of 0.1 V/Å can further decrease
the barrier by ∼2 kcal/mol. Partial solvation has a negligible
effect on lowering the activation barrier in microdroplets but can
increase the collision frequency between reactants. With acidity revealed
to be the major accelerating factor for methanol droplets, reactions
on water microdroplets should have even higher rates because water
is more acidic. Both theoretically and experimentally, we confirmed
that water microdroplets significantly accelerate the aza-Michael
reaction, achieving an acceleration factor that exceeds 107. This work elucidates the multifactorial influences on the microdroplet
acceleration mechanism, and with such detailed mechanistic investigations,
we anticipate that microdroplet chemistry will be an avenue rich in
opportunities in the realm of green synthesis.

微滴化学正逐渐成为加速反应的强大工具，其效果可达到数个数量级。据报道，极端的pH值、界面电场（IEFs）以及部分溶解等独特性质是导致加速反应的原因；然而，哪个因素起关键作用尚不明确。在本研究中，我们通过量子化学计算探索了甲基胺与丙烯酰胺之间亚甲-迈克尔加成反应的潜在机制。我们发现，甲醇微滴中的加速效应源于多个因素的累积效应。微滴的酸性表面起着主导作用，导致活化能降低约9 kcal/mol。我们推测，甲醇和微量水的解离共同贡献了表面的酸性。0.1 V/Å的界面电场可以进一步降低约2 kcal/mol的能垒。部分溶解对降低微滴中的活化能影响微乎其微，但可以增加反应物之间的碰撞频率。鉴于酸性已被揭示为甲醇微滴的主要加速因素，水微滴上的反应速率应更高，因为水的酸性更强。理论上和实验上，我们都证实了水微滴显著加速了亚甲-迈克尔反应，达到超过10^7的加速因子。这项工作阐明了多因素对微滴加速机制的影响，凭借如此详细的机制研究，我们预期微滴化学将在绿色合成领域开辟充满机遇的新路径。