Acylation of Amines, Part 3: In Situ Activation

This video is about the preparation of amides from carboxylic acids, amines, and some coupling or activating reagent. Because most carboxylic acids are stable and can be stored indefinitely, while acylating reagents may hydrolyze, chemists often feel more comfortable when activating carboxylic acids themselves, just before or during the acylation reaction. This can be done in a number of ways, and here I'll show you some examples of the most practical strategies.
In situ activation of carboxylic acids can be done either with reagents that would also react irreversibly with amines, and with reagents that react with carboxylate anions faster than with amines. In the former case, the acid must be activated first, and the amine must be added afterwards. But when using coupling reagents that react faster with carboxylates than with amines, these reagents can be added to a mixture of acid and amine.

Further examples:

Chloroformates:
Org. Lett. 2004, 6, 3675-3678;
Org. Proc. Res. Dev. 2003, 7, 888-895;
Org. Syn. 2014, 91, 137; 2011, 88, 317; 1988, 66, 132.

Sulfonyl chlorides:
Tetrahedron 1993, 49, 1535-1540;
J. Org. Chem. 1971, 36, 532-540;
J. Am. Chem. Soc. 1963, 85, 2446-2448.

Carbonyldiimidazole (CDI):
Org. Proc. Res. Dev. 2020, asap (Butler, DeForest); 2018, 22, 1294-1297 (acid catalysis); 207-211 (NH3); 2013, 17, 193-201; 2012, 16, 1832-1845; 2009, 13, 106-113 (acid catalysis); 60-63; 2005, 9, 956-961 (acid catalysis); 2004, 8, 1054-1058 (acid catalysis).

Phosphorus derivatives:
ACS Omega 2020, 5, 15734-15745 (R3PXY);
ACS Catal. 2020, 10, 10005-10009 (ATP, enzyme);
Tetrahedron Lett. 2019, 60, 151311 (P4O10);
Org. Proc. Res. Dev. 2011, 15, 1052-1062 (T3P);
Tetrahedron 2003, 59, 2325-2331 (Ph3PCl2).

Carbodiimides:
Org. Proc. Res. Dev. 2017, 21, 1602-1609 (large scale solid phase peptide synthesis); 2016, 20, 1104-1107 (aminoalcohols); 2015, 19, 1257-1262; 2014, 18, 1702-1713;
ChemistryOpen 2012, 1, 147-152 (comparison active esters);
Org. Proc. Res. Dev. 2009, 13, 310-314.

Other:
Green Chem. 2021, 23, 288-295 (Ph2SiH2);
Org. Lett. 2018, 20, 950-953 (Si(OMe)4);
Nature Comm. 2016, 7, 11732 (C2H2);
J. Org. Chem. 2013, 78, 4512-4523 (B(OR)3);
Synlett 2011, 2072-2074 (AlMe3); 2007, 1026-1030 (BH3);
Tetrahedron 2001, 57, 1551-1558 (triazines).

Reviews:
Org. Proc. Res. Dev. 2018, 22, 1262-1275 (thermal stability coupling reagents); 760-772 (peptides); 2016, 20, 140-177;
ARKIVOC 2010, viii, 189-250;
Tetrahedron 2005, 61, 10827-10852.