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Chemical compound
TCFH ("N","N","N"’,"N"’-tetramethylchloroformamidinium hexafluorophosphate) is an electrophilic amidine reagent used to activate a number of functional groups for reaction with nucleophilies. TCFH is most commonly used to activate carboxylic acids for reaction with amines in the context of amide bond formation and peptide synthesis. 
Preparation.
TCFH is commercially available. It may be prepared from tetramethylurea using a chlorinating agent such as oxalyl chloride, thionyl chloride or phosphorus oxychloride followed by salt exchange.
Uses.
TCFH itself is a common reagent used in the preparation of uronium and guanidinium salts used for amide bond formation and peptide synthesis, such as HATU.
Amide bond formation with TCFH can be performed in a wide range of organic solvents, most commonly acetonitrile, but also water and in the solid state. Reactions typically require an added Brønsted base, and a wide range can be employed including "N,N"-diisopropylethylamine (DIPEA). In reactions of carboxylic acids with TCFH and a weakly Lewis basic amine like DIPEA, formation of an acid chloride or anhydride as the active acylating agent occurs. Use of "N"-methylimidazole (NMI) as a base, with both Brønsted and Lewis basic properties, provides some unique advantages. Reactions of carboxylic acids with TCFH and a strongly Lewis basic amine like NMI lead to "in situ" formation of an "N"-acyl imidazolium ion (NAI) as the active acylating agent. 
These strongly electrophilic NAIs allow for reactions with a wide range of nitrogen nucleophiles, including hindered and electron-deficient amines. An added benefit of the use of NMI as the base, due to its low p"K"a(H2O) of 7, is that the epimerization of labile stereogenic centers is minimized. The reaction by-products have high water solubility, facilitating reaction workup and isolation. 
TCFH can also be used in other reactions involving activation of carboxylic acids from reactions with oxygen-, sulfur- and carbon-nucleophiles for the preparation of esters, thioesters and ketones. Extending beyond reactions with carboxylic acids, TCFH has been shown to be an activator for other oxygen centered nucleophiles, including heterocyclic alcohols, ketooximes, and even alcohols. Reactivity with sulfur centered nucleophiles like thioureas has also been demonstrated.
Safety.
TCFH does not exhibit dermal corrosion or irritation but irritates eyes. The sensitization potential of TCFH was shown to be low compared to other common amide bond forming agents (non-sensitizing at 1% in LLNA testing according to OECD 429). The by-product of the reactions of TCFH is tetramethylurea, which has demonstrated embryotoxic and teratogenic activity in several animal species.
References.
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