CO₂‐Enabled Cyanohydrin Synthesis and Facile Iterative Homologation Reactions**

Abstract

Thermodynamic andk inetic control of ac hemical process is the key to access desired products and states. Changes are made when ad esired product is not accessible;o ne may manipulate the reaction with additional reagents, catalysts and/or protecting groups. Here we report the use of carbon dioxide to accelerate cyanohydrin synthesis under neutral conditions with an insoluble cyanide source (KCN) without generating toxic HCN. Under inert atmosphere,t he reaction is essentially not operative due to the unfavored equilibrium. The utilityo f CO 2-mediated selective cyanohydrins ynthesis was further showcased by broadening Kiliani-Fischer synthesis under neutral conditions. This protocol offers an easy access to a variety of polyols, cyanohydrins, linear alkylnitriles, by simply starting from alkyl-a nd arylaldehydes, KCN and an atmospheric pressureo fC O 2. Achemical reaction is governed by kinetics and thermodynamics, and as imultaneous controlo fb oth parameters is a commonp ractice in designing and optimizing chemical reactions. The manipulation of thermodynamic stability of reactants and products will decide the outcome of ac hemical process, while variousr eactionp athways can lead to undesired products thus reducing overall efficiency of the process. [1] To circumvent unwanted reactionp athways, chemists have developed selectivec atalysis,p rotecting groups ("P" in Scheme1), trappingr eagents and reactivity-altered reactants (A' and B'), which in turn can limit the scopea nd generality of the original reaction. In our ongoing pursuit to implement CO 2 in the core of organic synthesis, we sought out ways in which equilibria can be controlled by the use of CO 2-a mild Lewis acid where anionic intermediates can be stabilized. Carbon dioxide is an intrinsicallys table molecule, [2, 3] however,i tc an readily and reversibly react with various nucleophiles. [2, 4] Recent applicationso fc arbond ioxide in organic synthesis showed fruitful successp articularly in CO 2-incorporation , [5] CO 2 as at emporal protecting group for CÀHa ctivation, [6] CO 2 for asymmetricc atalysis [7] and oxidation reactions. [8] We recently investigated the role of CO 2 in ac yanation reaction, [9] where CO 2 can be used in catalytic amountst of acilitate the stereoselective transformation of activated electrophiles via 1,4-conjugate addition reactions. Cyanohydrin synthesis À1,2-cyanide addition reactions to carbonyls-is one of the oldestC ÀCb ond-forming reactions using HCN as ac yanide source. [10] Despite the high utility of cyanohydrins in organic synthesis [11-14] the use of HCN reduces its application potential due to its volatile nature and health risks. Recent research activitiesi nc yanohydrin synthesis are mainly performed by using TMSCN 15] and cyanoformate [16] as aH CN surrogate. [11, 12, 17] These reagents suffer from poor atom economyw hen unprotected cyanohydrins are desired. Furthermore,t he cyanation reactions with in situ generated HCN (from am ixture of TMSCNa nd an alcohol) are limitedb yt he instability of the cyani...

Prebiotic photoredox synthesis from carbon dioxide and sulfite

“…At pH 9, both loss of hydroxide from HCO 3 − 1 and loss of water from its conjugate acid, H 2 CO 3 , furnish CO 2 . The latter process is efficiently catalyzed by nucleophiles 18 – 20 , especially sulfite 21 , so it is unlikely that the otherwise slow kinetics of equilibration limit the photoredox chemistry. Although the equilibrium concentration of CO 2 is very low in a solution containing HCO 3 − 1 at pH = 9 relative to the concentration of 1 ( Supplementary Fig.…”

A CO2-Mediated Conjugate Cyanide Addition to Chalcones

“…However, it is important to note that the employment of CO 2 can complicate the outcome of reactions due to undesired binding of nucleophiles therefore reducing the reactivity. Based on our investigation and previous studies [15,27,28], we presumed that the positive effects of CO 2 in catalyzing chemical reactions can be general, particularly in reactions involving reversible steps. In the current investigation with chalcones, the reaction is highly controlled by thermodynamics that allowed us to access various products in high yield.…”

CO2‐Mediated Non‐Destructive Cyanide Wastewater Treatment

“…[10] Our recent research on the reaction of cyanides with aldehydes under a CO 2 atmosphere revealed the facile formation of cyanohydrins where a variety of solvents including protic solvents could afford high yields of cyanohydrins. [11] It is important to note here that the cyanide addition reactions are often sluggish and unselective, however, can be accelerated with the use of CO 2 (Scheme 2). [12] This led us to invert our focus and measure the ability of aldehydes and CO 2 to remove cyanide from water as a method of purification.…”

“…While the equilibrium typically favors the aldehyde under neutral pHs, we previously found that in the presence of CO 2 the equilibrium is shifted towards the cyanohydrin. [11] This is exemplified by benzaldehyde which is efficiently converted to benzaldehyde cyanohydrin (mandelonitrile) by the reaction with NaCN in water under a CO 2 atmosphere (1 atm). Mandelonitrile was separated from the aqueous phase, allowing for easy isolation of the aqueous phase.…”

“…Throughout our investigation into CO 2 -mediated cyanohydrin synthesis we observed that ortho-substituted benzaldehydes gave superior yields without sophisticated purification compared to reported procedures. [11] It is reported that ortho-substituents on aromatic aldehydes can increase the stability of the corresponding cyanohydrins, preventing side reactions due to the steric hindrance. [14] Among the orthosubstituted benzaldehydes 2-methoxybenzaldehyde portrayed several interesting characteristics: synthetically accessible and easy to purify.…”