Chemical Properties
YELLOW TO ORANGE FINE CRYSTALLINE POWDER
Uses
It finds its application as a reagent for protection of carboxyl termini of peptides as 4-picolyl esters, providing a polar 'handle' which aids in separation and purification of the peptide. The group can be introduced in the presence of a base, e.g. tetramethylguanidine, is stable to acid-catalyzed removal of Cbz protecting group and can be removed by base, Na in liquid ammonia or catalytic hydrogenolysis. It is also applied in conjunction with Amberlyst15 resin in peptide synthesis. It is an important raw material and intermediate used in organic synthesis, pharmaceuticals and agrochemicals.
Application
4-Picolyl Chloride Hydrochloride is used for protection of alcohols, phenols, thiols, and carboxylic acids.
Synthesis
Synthesis of 4-chloromethylpyridine hydrochloride (21): 4-Pyridine methanol (20) (54.4 g, 0.50 mol) was dissolved in 202 ml of acetonitrile. The solution was slowly added dropwise to a mixed solution containing thionyl chloride (65.3 g, 0.55 mol) and acetonitrile (109 ml) at 50 °C. After the dropwise addition was completed, the reaction mixture was continued to be stirred at 50 °C for 1 hour. After completion of the reaction, the mixture was cooled to room temperature to give a slurry product (quantitative yield) of 4-chloromethylpyridine hydrochloride (21). The product was characterized by 1H-NMR (DMSO-d6, with TMS as internal standard): δ 5.09 (s, 2H), 8.09 (d, J = 6.6 Hz, 2H), 8.94 (d, J = 6.6 Hz, 2H).
storage
The free base is reported to be unstable, and should be
generated shortly before use.
Purification Methods
Purify it by recrystallisation from EtOH or EtOH/dry Et2O. It melts between 171o and 175o, and the clear melt resolidifies on further heating at 190o and turns red to black at 280o but does not melt again. The picrate-hydrochloride (prepared in EtOH) has m 146-147o. The free base is an oil. [Mosher & Tessieri J Am Chem Soc 73 4925 1951, Beilstein 20 III/IV 2752.]
References
[1] Patent: US2003/195363, 2003, A1. Location in patent: Page/Page column 13
[2] Patent: US6057448, 2000, A
[3] ChemMedChem, 2015, vol. 10, # 11, p. 1875 - 1883
