DIPEA-induced activation of OH− for the synthesis of amides via photocatalysis

The development of green protocols for photocatalysis where water acts as a nucleophile, induced by a weak organic base, is difficult to achieve in organic chemistry. Herein, an efficient light-mediated strategy for the synthesis of amides in which a weak organic base acts as a reductant to induce the formation of OH– from water under metal-free conditions is reported. A mechanistic study reveals that the generation of an N,N-diisopropylethylamine (DIPEA) radical via single electron transfer (SET), with the assistance of photocatalyst, that increases the nucleophilicity of the water molecules with respect to the cyanides is essential. Moreover, the removal rate of nitrile in wastewater can be as high as 83%, indicating that this strategy has excellent potential for nitrile degradation.

Under weak organic base condition DIPEA as a reductant to increase the nucleophilicity of H₂O an excellent potential system for nitrile degradation.

The synthesis of amides is a subject of continuous interest and great importance because of their important applications in detergents, agrochemicals, polymers and pharmaceuticals.¹ Traditional methods for their synthesis require the transformation of an acid into the corresponding acyl chloride, facilitated by the use of the Schotten–Baumann reaction.² Although these methods produce amides in good yields, stoichiometric amounts of an activating reagent are required, making these poorly atom economic processes. Various strategies for carboxamide synthesis, such as oxidative alcohol–amine and aldehyde–amine coupling reactions, amine dehydrogenation or oxidation reactions, and C–N coupling reactions, have been developed in recent years.³ Despite this, one of the most straightforward and atom-economical ways to synthesize amides remains the hydration of organonitriles.⁴ Conventional strategies mostly use strong inorganic bases to generate strongly nucleophilic hydroxide ions, require tough conditions, and are sensitive, especially when using bioactive molecules,⁵ to the substrate. Moreover, water molecules are usually used as nucleophiles in the hydration of nitriles. Thus, compared to the use of strong basic conditions, the direct nucleophilic addition of water to the cyano group is kinetically slow due to the high energy of the carbon–nitrogen triple bond.⁶ To circumvent these problems, transition metal (TM) catalytic procedures, where the metal center of the catalyst acts as a Lewis acid to activate the nitrile and the ligand acts as a Lewis base-activated nucleophile, have been developed in recent years.⁷ But these protocols are associated with certain debilitating disadvantages that include the presence of toxic transition metal cations within the molecular structure of the reagents and difficulties in preventing over-hydrolysis to the corresponding carboxylic acids.Recently, there have been some reports that reductants have been used to change the morphology of water to increase its nucleophilicity.⁸ Organoamine bases, such as N,N-diisopropylethylamine (DIPEA), have acted in the role of both base and nitrogen radical intermediate and are considered to be reductants.⁹ However, DIPEA does not lose electrons easily and therefore has a low reductive activity, which means the nitrogen center has to cross a higher energetic barrier. Recently, it was shown that DIPEA could reductively quench many excited photocatalysts by single electron transfer (SET) to generate nitrogen-centered radicals.¹⁰ For example, Xu and coworkers¹¹ proposed a new approach using DIPEA to construct difluoroalkylated diarylmethane compounds via visible light photocatalytic radical–radical cross-coupling reactions, in which DIPEA can carry out electron transfer due to the induction of the photocatalyst. It indicates that photooxidation–reduction and organic amine reduction are, when exposed to sufficient light intensity, co-catalytic processes and can generate nitrogen-centered radicals so that the downstream reaction process can continue.¹² Herein, an efficient light-mediated strategy for the synthesis of amides in which a weak organic base acts as a reductant to induce the formation of OH– from water under metal-free conditions is reported.Initially, the reaction of the benzonitrile (1a) was selected for the screening of the reaction conditions (Fig. 1, ​,22 and ​and33.Optimization of the reaction conditions^a

Entry	Variations from the standard conditions	Yieldb (%)
1	None	89
2	Eosin B instead of eosin Y	41
3	Rose bengal instead of eosin Y	73
4	Rhodamine B instead of eosin Y	Trace
5	Erythrosin B instead of eosin Y	78
6	TEA instead of DIPEA	64
7	DABCO instead of DIPEA	13
8	DMSO/H2O (1/2) instead of H2O 3 mL	54
9	DMF/H2O (1/2) instead of H2O 3 mL	27
10	12 h instead of 24 h	47
11	28 h instead of 24 h	90
12	Blue light 5 W instead of blue light 12 W	63
13	White light instead of blue light	43
14	DIPEA 1.0 equiv. instead of 2.0 equiv.	59
15c	Gram-scale experiment	72

Open in a separate window^aStandard conditions: 1a (0.5 mmol), DIPEA (2.0 equiv.), eosin Y (0.1 equiv.), blue light, 12 W, H₂O 3 mL, 24 h, rt.^bIsolated yield.^c10 mmol 1a, 15 equiv. DIPEA and 0.1 equiv. eosin Y, blue light 12 W, H₂O 25 mL 36 h.Open in a separate windowFig. 1General methods for the hydration of organonitriles.Open in a separate windowFig. 2Pharmaceuticals and biomolecules containing a primary amide functional group.Open in a separate windowFig. 3Variation of removal rate of nitrile at different reaction times.With the optimized conditions in hand, the substrate scope was investigated (