9-Fluorenylmethyloxycarbonyl chloride

April 26, 2021
If you’re an amine, you may need my protection.
What molecule am I?

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). 

9-Fluorenylmethyloxycarbonyl chloride
hazard information

Hazard class** Hazard statement
Corrosive to metals, category 1 H290—May be corrosive to metals Chemical Safety Warning
Acute toxicity, oral, category 4 H302—Harmful if swallowed Chemical Safety Warning
Acute toxicity, dermal, category 4 H312—Harmful in contact with skin Chemical Safety Warning
Skin corrosion/irritation, category 1B H314—Causes severe skin burns and eye damage Chemical Safety Warning
Serious eye damage/eye irritation, category 1 H318—Causes serious eye damage Chemical Safety Warning
Acute toxicity, inhalation (dusts/mists), category 4 H332—Harmful if inhaled Chemical Safety Warning
Specific target organ toxicity, single exposure, respiratory tract irritation, category 3 H335—May cause respiratory irritation Chemical Safety Warning

*Compilation of multiple safety data sheets.
**Globally Harmonized System of Classification and Labeling of Chemicals.  
Explanation of pictograms.

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9-Fluorenylmethyloxycarbonyl chloride fast facts

CAS Reg. No. 28920-43-6
SciFinder
nomenclature
Carbonochloridic acid, 9H-fluoren-9-ylmethyl ester
Empirical formula C15H11ClO2
Molar mass 258.70 g/mol
Appearance White to off-white crystalline powder
Melting point 62–64 ºC
Water solubility Insoluble; decomposes

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