Abstract
Density functional theory calculations elucidated the precise reaction mechanism for the conversion of diphenylacetylenes into benzonitriles involving the cleavage of the triple C≡C bond, with N-iodosuccinimide (NIS) as an oxidant and trimethylsilyl azide (TMSN3) as a nitrogen donor. The reaction requires six steps with the activation barrier ΔG‡ = 33.5 kcal mol−1 and a highly exergonic reaction free-energy ΔGR = −191.9 kcal mol−1 in MeCN. Reaction profiles agree with several experimental observations, offering evidence for the formation of molecular I2, interpreting the necessity to increase the temperature to finalize the reaction, and revealing thermodynamic aspects allowing higher yields for alkynes with para-electron-donating groups. In addition, the proposed mechanism indicates usefulness of this concept for both internal and terminal alkynes, eliminates the option to replace NIS by its Cl- or Br-analogues, and strongly promotes NaN3 as an alternative to TMSN3. Lastly, our results advise increasing the solvent polarity as another route to advance this metal-free strategy towards more efficient processes.
Highlights
IN3 is not prone to a simple substitution, which differs from the proposal by Yanada (Scheme 1), as all of our attempts to model such a process gave no suitable transition states or intermediates, typically resulting in the breaking of the strained azirine ring. We considered both the SN1 reaction possibility, which did not provide a favorable cleavage of the C–I bond in IN3, and the SN2 reaction alternative with either TMSN3 or its even more nucleophilic azide
We can conclude that the reaction with NaN3 proceeds through only four steps with the rate-limiting process identical to that when TMSN3 is used yet being significantly thermodynamically more favored. This justifies Yanada’s statement that “the use of sodium azide instead of TMSN3 was found effective for the triple bond cleavage reaction” [22], knowing that the use of NaN3 offered comparable nitrile’s yields, but without the need to heat the mixture above room temperature to finish the reaction, as was the case with TMSN3
We confirmed that para-electron-donating groups facilitate the reaction, but showed this is not a kinetic effect channelized through the substituent electronic contributions, but rather a thermodynamic effect seen in the highest ∆GR = −192.0 kcal mol−1 for the p-Me derivative 2, to be reduced to −191.9 and −188.8 kcal mol−1 in the unsubstituted
Summary
The transformation of alkynes is a fundamental method that has been widely used in organic synthesis [1,2,3,4,5] to afford ketones [6,7], diketones [8,9], acids and their derivatives [10,11,12], alkyl or alkenyl halides [13,14], cycloalkanes or cycloalkenes [15,16,17], and nitriles [18,19,20,21,22,23,24,25], which makes these processes highly appealing in academic research and industrial applications [5]. The cyano group is ubiquitous in useful natural products, Conventional methods to access nitriles, such as the Sandmeyer [45] and Rosenmund pharmaceuticals, top-selling agricultural chemicals, functional materials, and dyeswith von Braundrugs, reactions [46,47], or transition-metal-mediated cyanation of aryl halides [38,39,40,41,42,43,44]. Our out the textprovide are presented in Figure calculations show different mechanistic routes to those proposed by Yanada [22] and reveal a very modest electronic effect of the para-EDG substituents on the reaction outcomes while offering guidelines to advance this reaction strategy and design new catalytic reaction systems towards even more efficient transformations
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