9-Fluorenylmethyl chloroformate

Description

Protecting groups are a fundamental tool in organic synthesis. In general, a protecting group is used to “protect” an otherwise labile or reactive functional group from interfering in subsequent steps of a synthesis. When this protection is no longer needed, a suitable reagent is used to “deprotect” the protected moiety.
Amines constitute one of the more common functional groups that need to be protected during a synthesis. In 1970, Louis A. Carpino* and Grace Y. Han at the University of Massachusetts (Amherst) noted, “In contrast to the variety of amino-protecting groups [that] can be cleaved . . . by acids of varying strengths, there is currently no complementary set of groups cleavable by basic reagents of graded activity.” They went on to introduce the 9-fluorenylmethyloxycarbonyl (Fmoc) group that, once no longer needed, can be removed under basic conditions.
The reagent the researchers chose to install the Fmoc group was 9-fluorenylmethyloxycarbonyl chloride (Fmoc-Cl), also frequently called 9-fluorenylmethyl chloroformate. They prepared Fmoc-Cl by treating 9-fluorenylmethanol with phosgene (COCl2). As an alternative to Fmoc-Cl, they prepared the corresponding 9-fluorenylmethyl azidoformate, which they made via the reaction of Fmoc-Cl with sodium azide (NaN3).
In an initial example of amine protection/deprotection, Carpino and Han treated glycine with Fmoc-Cl. They then showed that treating the resulting Fmoc derivative with liquid ammonia quantitatively releases the original amine, along with the easily separable byproducts carbon dioxide and dibenzofulvalene.
In a subsequent publication, Carpino and Han discussed the shortcomings of other protecting groups that they examined before they came upon the Fmoc group. They also provided numerous examples of Fmoc-protected amino acids, amino esters, and dipeptides. Finally, they demonstrated that strong organic amines such as piperidine, morpholine, and ethanolamine can be used in place of ammonia to remove Fmoc.
Carpino and Han went on to patent Fmoc-Cl and other Fmoc derivatives as compounds useful in peptide synthesis and for separating optical isomers (US Patent 3,835,175, Sept. 10, 1974). A subsequent patent (US Patent 3,906,031, Sept. 16, 1975) claimed Fmoc-protected amino acids, particularly phenylalanine. Both patents were assigned to Research Corp. (New York).

Chemical properties

White to off white crystalline powder

The Uses of 9-Fluorenylmethyl chloroformate

9-Fluorenylmethyl chloroformate is an N-Protecting agent for peptides research and was used for the pre-column derivatization of the biogenic amines (BAs) cadaverine (Cad), histamine (Him), octopami ne (Ocp), phenylethylamine (Pea), putrescine (Put), spermidine (Spd), spermine (Spm), tyramine (Tym).

The Uses of 9-Fluorenylmethyl chloroformate

9-Fluorenylmethyl chloroformate can be used as N-protecting reagent for oligonucleotide and peptide syntheses.

The Uses of 9-Fluorenylmethyl chloroformate

9-Fluorenylmethyl chloroformate can act as reagent for the introduction of Fmoc-amino-protecting group, which is stable towards acids but is readily cleaved under mildly basic non-hydrolytic conditions.

What are the applications of Application

Fmoc chloride is used for the precolumn derivatization of amines

General Description

Fmoc chloride is a derivatizing agent.

Flammability and Explosibility

Not classified

Safety Profile

A poison. Mutation data reported. A corrosive. When heated to decomposition it emits toxic vapors of Cl-.

Purification Methods

If the IR contains no OH bands (at ~3000 cm-1) due to the hydrolysis product 9-fluorenylmethanol, then purify it by recrystallisation from dry Et2O. IR (CHCl3) has a band at 1770 cm-1 (C=O), and the NMR (CDCl3) has  at 4-4.6 (m 2H, CHCH2) and 7.1-7.8 (m, 8 aromatic H) ppm. The azide (FMOC-N3) has m 89-90o (from -1hexane) and IR (CHCl3) at 2135 (N3) and 1730 (C=O) cm , and the carbazate (FMOC-NHNH2) has m 171o(dec) (from nitromethane), IR (KBr) 3310, 3202 (NH) and 1686 (CONH) cm-1. [Caprino & Han J Org Chem 37, 3404 1972 , J Am Chem Soc 92 5748 1970, Koole et al. J Org Chem 59 1657 1989, Fürst et al. J Chromatogr 499 537 1990.]