Tetrabutylammonium fluoride trihydrate is a mild base used in reactions like aldol-type condensation reactions, Michael-type reactions, ring-opening reactions. Its is also used as a promoter in cross-coupling reactions and cyclization of carbocycles and heterocycles.

Synthesis of Glycopeptide Partial Structures

The (2-phenyl-2-trimethylsilyl)ethyl-(PTMSEL) linker represents a novel fluoride-sensitive anchor for the solid-phase synthesis of protected peptides and glycopeptides. Its cleavage is achieved under almost neutral conditions using tetrabutylammonium fluoride trihydrate in dichloromethane thus allowing the construction of complex molecules sensitive to basic and acidic media commonly required for the cleavage of standard linker systems. Recently, the (2-phenyl-2-trimethylsilyl)ethyl-(PTMSEL)-linker was introduced as a fluoride-labile linker for the solid-phase synthesis of protected peptides and glycopeptides according to Fmoc chemistry. Cleavage of the PTMSEL-linker is achieved under almost neutral conditions by treatment with tetrabutylammonium fluoride trihydrate (TBAF?3?H2O) in dichloromethane.Other fluoride-labile anchors, such as p-silylmethyl-benzyl, p-silyloxy-benzyl and α-trimethylsilyl-benzyl (SAC) linkers, require much more basic cleavage conditions, for example TBAF?3?H2O in dimethylformamide or tetrahydrofuran; these conditions are not compatible for retaining the Fmoc group.[1]

The glycosylated building block Fmoc-Asn(βAc3GlcNAc-βAc3GlcNAc)-OH (3 equiv) was coupled manually using O-(7-aza-benzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium-hexafluorophosphate (HATU) /N-hydroxy-7-azabenzotriazole (HOAt). After completion of the automated peptide synthesis, the glycopeptide was released from the solid support by two sequential treatments with two equivalents of tetrabutylammonium fluoride trihydrate (TBAF?3?H2O) in dichloromethane. The glycoconjugate was liberated from the resin by treatment with TBAF?3?H2O in dichloromethane to furnish the selectively deblocked derivative in a yield of 42?% after preparative HPLC (based on the preloaded resin ). Only traces of side products were observed, and no aspartimide formation and rearrangements could be detected. The solid-phase syntheses of complex glycopeptides from the LI-cadherin and mucin series have been accomplished using the novel (2-phenyl-2-trimethylsilyl)ethyl-(PTMSEL)-linker. Its cleavage under almost neutral conditions by tetrabutylammonium fluoride trihydrate in dichloromethane has been shown to have advantages over other common linkers.

Reactivity and Selectivity in Cellulose Functionalization

A variety of new cellulose solvents was investigated toward their potential as media for the functionalization of the polyglucane. Thus, mixtures of dimethyl sulfoxide (DMSO)/tetrabutylammonium fluoride trihydrate (TBAF), N-methylmorpholine-N-oxide (NMMNO)/DMSO, melts of LiClO4·3H2O, and aqueous solutions of Ni(tren)(OH)2 [tren = tris(2-aminoethyl)amine] were applied as reaction media.A mixture of DMSO/TBAF represents an efficient cellulose solvent. It dissolves the polymer with a degree of polymerization (DP) of up to 650 within 15 min completely. No pretreatment is necessary. The solutions applied in this study contained 16.6% (w/v) tetrabutylammonium fluoride trihydrat and 2.9% (w/v) cellulose. In 13C NMR spectra signals appear at 102.7 (C-1), 78.4 (C-4), 75.6 (C-5), 75.0 (C-3), 73.5 (C-2), and 59.9 ppm (C-6) only. In a first series of experiments, the cellulose dissolved in DMSO/TBAF was treated with acetic anhydride. If a molar ratio of 2.3:1.0 (acylation reagent/anhydroglucose unit, AGU) is applied, a DS value of 0.83 was determined.[2]

Not only the high reactivity of the cellulose dissolved in DMSO/TBAF yielding derivatives with DS values as high as 2.09 in one step but also the structures obtained are in good agreement with findings for carboxymethylation reactions in DMAc/LiCl. This result is surprising because the reaction mixture contains a rather high amount of water (62.7 mmol) resulting both from the nondried cellulose and the tetrabutylammonium fluoride trihydrat trihydrate used. In contrast, only traces of water lead to products with a completely statistic distribution of ether functions along the chain under comparable etherification conditions starting from organo-soluble cellulose derivatives with limited hydrolytic stability. Thus, it can be concluded that the solvent DMSO/ tetrabutylammonium fluoride trihydrat is the most reactive for the carboxymethylation although the conversion is not totally homogeneous. The homogeneous reaction in Ni(tren)(OH)2 yields the lowest DS. Furthermore, the solvents DMSO/TBAF and NMMNO/DMSO can be applied for the preparation of CMC with a nonstatistic distribution of functional groups along the chain as already known for conversions of cellulose dissolved in DMAc/LiCl or starting from organo-soluble derivative of cellulose of limited hydrolytic stability dissolved in DMSO.

Dimethyl Sulfoxide/Tetrabutylammonium Fluoride Trihydrate

Cellulose is a versatile starting material for chemical conversions aiming to a variety of cellulose derivatives used in many areas of industry and domestic life. The novel solvent dimethyl sulfoxide (DMSO)/tetrabutylammonium fluoride trihydrate (TBAF?·?3H2O) was studied for acetylation of linters cellulose. In order to control the degree of substitution (DS), acetylation of the macromolecule was carried out at different reaction time and temperature, molar ratio of reactants, as well as under variation of the concentration of TBAF?·?3H2O in solution. It was described that DMSO in combination with TBAF?·?3H2O dissolves cellulose very easily within 15 min at room temperature without any pre-treatment. In this work, we studied the acetylation of linters cellulose (a cellulose material derived from cotton) with 440 dissolved in DMSO/ tetrabutylammonium fluoride trihydrate. 

The influence of the solvent-mixture concerning the ratio TBAF?·?3H2O to cellulose on the DS values of the samples was studied. Although the mechanism of dissolution of cellulose in DMSO/TBAF?·?3H2O is not known in detail up to now, it may be proposed that water has an important role in this process, as it occurs also for another solvent-systems, as for instance DMAc/LiCl.At concentrations of TBAF from 13% to 20%, the products show an increasing DS while a further increase of TBAF (up to 33%) leads to products of lower DS.The results presented show that DMSO/TBAF?·?3H2O is a suitable reaction medium for the homogeneous acetylation of cotton linters cellulose and broadens the possibilities for homogeneous phase chemistry of cellulose.[3]

References

[1]Wagner, Michael et al. “The (2-phenyl-2-trimethylsilyl)ethyl-(PTMSEL)-linker in the synthesis of glycopeptide partial structures of complex cell surface glycoproteins.” Chemistry (Weinheim an der Bergstrasse, Germany) vol. 9,24 (2003): 6018-30. doi:10.1002/chem.200305304

[2]Liebert, T F, and T J Heinze. “Exploitation of reactivity and selectivity in cellulose functionalization using unconventional media for the design of products showing new superstructures.” Biomacromolecules vol. 2,4 (2001): 1124-32. doi:10.1021/bm010068m

[3]Ass, Beatriz A P et al. “Studies on the homogeneous acetylation of cellulose in the novel solvent dimethyl sulfoxide/tetrabutylammonium fluoride trihydrate.” Macromolecular bioscience vol. 4,11 (2004): 1008-13. doi:10.1002/mabi.200400088