1,3-Bis(2,2-dimethyl-1,3-dioxolan-4-ylmethyl)carbodiimide (BDDC)

[159390-26-8]  · C13H22N2O4  · (MW 270.32)

(reagent for clean, efficient peptide coupling, esterification and dehydration)

Physical Data: bp 115-125 °C (<1 mmHg); density 1.062 g mL-1

Solubility: most organic solvents.

Form Supplied in: pale yellow oil; commercially available.

Purification: distill at <1 mmHg.

Handling, Storage, and Precautions: material should be stored under a dry atmosphere of Ar or N2 at 0 °C. Many carbodiimides are strong sensitizers, therefore 1,3-bis(2,2-dimethyl-1,3-dioxolan-4-ylmethyl)carbodiimide (BDDC) should be considered as such. Avoid all skin contact, and use proper personal protection equipment (gloves, goggles, lab coat, etc.). BDDC should only be used in a well-ventilated fume hood. BDDC is incompatible with strong acids, including aqueous acids. BDDC is flammable; avoid fire or sparks. Decomposes upon prolonged storage at room temperature and exposure to air and moisture.

Preparative Methods: BDDC can be purchased commercially or it can be easily made in the laboratory from 3-aminomethyl-2,2-dimethyl-1,3-dioxolane.1

Residue-Free Reactions

BDDC performs peptide couplings, esterifications, and dehydrations similar to the well known carbodiimides dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDC),2 but is designed to be easily removed from reaction mixtures with dilute acidic washes (1).1 BDDC and its by-products are highly hydrophilic allowing for easy removal from organic systems with dilute aqueous acid washes, unlike DCC or DIC. In addition, the neutral structure of BDDC gives it enhanced solubility in organic solvents, and makes it less sensitive to moisture as compared to EDC.

Peptide Couplings

BDDC is an excellent reagent for the coupling of amino acids to form peptide bonds (2). The reagent affords good yields of dipeptides and tripeptides under typical coupling conditions with minimal racemization. When combined with CuCl2, even amide protected C-terminus couplings give no racemization. All carbodiimide residues are removed from the reaction mixture with a simple aqueous acid wash, eliminating the need for chromatography.

Esterifications

Many methods are known for esterifying carboxylic acids.3 Strongly acidic or basic methods dominate these methods. One essentially neutral method is to employ an isourea (3).4 BDDC easily forms isoureas in nearly quantitative yield under mild conditions, unlike DCC, DIC, or EDC.1

The resulting isoureas convert carboxylic acids cleanly to the corresponding esters without the use of harshly acidic or basic reagents (4).

This is desirable when sensitive functional groups are present in the molecule and racemization must be avoided. The isourea reacts at the oxygen center, and not the carbonyl, so a-racemization cannot occur.

Dehydrations

Carbodiimides are also employed as general dehydrating agents.2 BDDC was used to dehydrate benzyl 3-hydroxybutanoate to benzyl crotonate in 83% yield.

Related Reagents.

dicyclohexylcarbodiimide (DCC); diisopropylcarbodiimide (DIC); 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDC).


1. Gibson, F.; Park, M.; Rapoport, H., J. Org. Chem. 1994, 59, 7503.
2. (a) Williams, A.; Ibrahim, I. T., Chem. Rev. 1981, 81, 589. (b) Mikolajczyk, M.; Kielbasinski, P., Tetrahedron 1981, 37, 233. (c) Kurzer, F.; Douraghi-Zahdeh, D., Chem. Rev. 1967, 67, 107.
3. Greene, T.; Wuts, P., Protective Groups in Organic Synthesis, 3rd edn; Wiley Interscience: Chichester, 1999, pp 372-428.
4. Mathias, L., Synthesis 1979, 561.

Frank Gibson

Bristol-Myers Squibb, New Brunswick, New Jersey, USA



Copyright 1995-2000 by John Wiley & Sons, Ltd. All rights reserved.