1,3-Diisopropylcarbodiimide

1,3-Diiscaropropylcarbodiimide, often abbreviated to DIC, DIPC or DIPCDI, is a coupling agent often used widely in organic chemistry for the synthesis of amides, peptides, esters and various heterocycles.

Carbodiimide based reagents have been routinely used in peptide chemistry for the formation of amide bonds since the introduction of dicyclohexylcarbodiimide (DCC) and its use in combination with the racemisation suppressing additive 1-hydroxybenzotriazole (HOBt )^1,2 and more recently 2-hydroxypyridine N-oxide (HOPO, product code FH05522)³. DIC is a clear liquid (bp 145-148°C) which makes it easier to handle than the low melting point solid DCC; an additional advantage is that the diisopropylurea byproduct formed during the coupling reaction is more soluble in dichloromethane than that formed if DCC is used. This makes DIC a more suitable coupling agent for use in solid-phase peptide synthesis, where urea byproduct insolubility has proved to be problematic.^4,5 The general mechanism for the formation of amides or peptides is shown in Scheme 1, and proceeds via the formation of an O-acylisourea intermediate 1. This activated ester subsequently reacts with an amine nucleophile to form the amide bond and diisopropylurea 2. The major side-reaction is a rearrangement of 1 to an N-acylurea, but this is effectively suppressed by the use of solvents such as dichloromethane or chloroform.

Carpino and El-Faham have demonstrated that the combination of DIC with the additive HOAt (Figure 1) has advantages over DIC / HOBt for peptide coupling reactions, with very little, if any racemisation occurring in CH₂Cl₂ solvent.⁶ The effective coupling of N-methylated, sterically hindered amino acids under solid-phase conditions has also been reported using this combination.⁷ The enhanced reactivity of HOAt over HOBt has been postulated to be due to the effect of the neighbouring nitrogen atom.⁸ The additional development of a stepwise procedure for peptide synthesis in which the hindered base collidine is added as an activation enhancer followed by diisopropylethylamine to enhance coupling has also been described.⁶ Ramage has also investigated the triazole based additive HOCt in combination with DIC and reported negligible racemisation with all amino acids except histidine.⁹


In a similar fashion to the synthesis of amide bonds, DIC can also be used to form esters from carboxylic acids via activated ester intermediate 1, as illustrated in Scheme 2.¹⁰

Guzzo and co-workers have reported the synthesis of optically active (acyloxy)alkyl esters via a coupling and rearrangement reaction mediated by DIC, Scheme 3.¹¹ The coupling step proceeds via unsymmetrical diacylperoxide 3 which then rearranges with the loss of carbon dioxide to yield 4. (Acyloxy)alkyl esters 4 have utility as prodrugs of carboxylic acid containing compounds.
DIC is widely used as a dehydrating agent in the synthesis of a diverse range of heterocycles. Recent examples (Scheme 4) include the formation of dihydroquinazolines (5) on solid-phase using DIC and HOBt,¹² synthesis of 2-oxazolines (6) from N-(b-hydroxyl)amides¹³ and trisubstituted imidazolidinones (7).¹⁴
References:

1. Sheehan, J. C.; Hess, G. P. J. Am. Chem. Soc. 1955, 77, 1067.
2. Konig, W.; Geiger, R. Chem. Ber. 1970, 103, 788.
3. Guo-Jie H. et al. J. Org. Chem. 1995, 60, 3569.
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5. Orlowska, A.; Holodowicz, E.; Drabarek, S. Pol. J. Chem. 1982, 56, 1067.
6. Carpino, L. A.; El-Faham, A. Tetrahedron 1999, 55, 6813.
7. Angell, Y. M.; García-Echeverría, C.; Rich, D. H. Tetrahedron Lett. 1994, 35, 5981.
8. Carpino, L. A. J. Am. Chem. Soc. 1993, 115, 4397.
9. Robertson, N.; Jiang, L.; Ramage, R. Tetrahedron 1999, 55, 2713.
10. Corbett, A. D.; Gleason, J. L. Tetrahedron Lett. 2002, 43, 1369.
11. Guzzo, P. R.; Dinn, S. R.; Lu, J.; Oettinger-Loomis, S. Tetrahedron Lett. 2002, 43, 5685.
12. Song, A.; Marik, J.; Lam, K. S. Tetrahedron Lett. 2004, 45, 2727.
13. Crosignani, S.; Young, A. C.; Linclau, B. Tetrahedron Lett. 2004, 45, 9611.
14. Wang, X.; Dixon, S.; Yao, N.; Kurth, M. J.; Lam, K. S. Tetrahedron Lett. 2005, 46, 5747.