real-time-monitoring-reactions-performed-using-continuous-flow

Real-time Monitoring of Reactions Performed Using Continuous-flow Processing: The Preparation of 3-Acetylcoumarin as an Example

By using inline monitoring, it is possible to optimize reactions performed using continuous-flow processing in a simple and rapid way. It is also possible ...

University of Connecticut

A simple, mild method for the oxidation of α-trifluoromethyl alcohols to trifluoromethyl ketones (TFMKs) using the oxoammonium salt 4-acetylamino-2,2,6,6-tetramethylpiperidine-1-oxoammonium tetrafluoroborate (1) is described. Under basic conditions, oxidation proceeds rapidly and affords good to excellent yields of TFMKs, without concomitant formation of the hydrate. The byproduct of the oxidation, 4-acetylamino-2,2,6,6-tetramethyl-1-piperidinyloxy (1c), is easily recovered and can be conveniently reoxidized to regenerate the oxoammonium salt.

Oxidation of α-trifluoromethyl alcohols using a recyclable oxoammonium salt.

An apparatus is reported for real-time Raman monitoring of reactions performed using continuous-flow processing. Its capability is assessed by studying four reactions, all involving formation of products bearing α,β-unsaturated carbonyl moieties; synthesis of 3-acetylcoumarin, Knoevenagel and Claisen-Schmidt condensations, and a Biginelli reaction. In each case it is possible to monitor the reactions and also in one case, by means of a calibration curve, determine product conversion from Raman spectral data as corroborated by data obtained using NMR spectroscopy.

Raman spectroscopy as a tool for monitoring mesoscale continuous-flow organic synthesis: Equipment interface and assessment in four medicinally-relevant reactions.

Oxoammonium salt oxidations (using 4-acetylamino-2,2,6,6-tetramethylpiperidine-1-oxoammonium tetrafluoroborate) of alcohols containing a β-oxygen atom in the presence of pyridine yield dimeric esters, while in the presence of 2,6-lutidine the product is a simple aldehyde. The formation of a betaine between pyridine and an aldehyde is presented to explain this disparity in reactivity. The betaine is oxidized by the oxoammonium salt to give an N-acylpyridinium ion that serves as an acylating agent for ester formation. Steric effects deter the formation of such a betaine with 2,6-disubstituted pyridines. A series of alcohols containing a β-oxygen substituent were oxidized to aldehydes in the presence of 2,6-lutidine, and a short study of the relative reactivity of various alcohols is given. An overall mechanism for oxoammonium cation oxidations is suggested, premised on nucleophilic additions to the oxygen atom of the positively charged nitrogen-oxygen double bond. Possible mechanisms for both dimeric oxidations and simple oxidations are given.

Oxoammonium salt oxidations of alcohols in the presence of pyridine bases.

An operationally simple, inexpensive, and rapid route for the olefination of a wide array of trifluoromethyl ketones to yield 3,3,3-trifluoromethylpropenes is reported. Using a Peterson olefination approach, the reaction gives good to excellent yields of the alkene products and can be performed without purification of the β-hydroxysilyl intermediate. The reaction can be extended to other perfluoroalkyl substituents and is easily scaled up. The alkenes prepared can be readily transformed into a variety of other perfluoroalkyl-containing compounds.

Methylenation of perfluoroalkyl ketones using a Peterson olefination approach.

The stabilizing features of a macrocyclic sesquiterpene-derived cation were explored using quantum mechanical calculations. The monocyclic humulyl cation, the product of 11,1-cyclization of farnesyl diphosphate, is the product of the first committed step in the enzymatic synthesis of a range of structurally diverse sesquiterpenes, including humulene (monocyclic); caryophyllene (bicyclic); and protoilludene, pentalenene, and isocomene (tricyclic). These natural products are formed via carbocation cascades that are directed in part by the conformation of the humulyl cation. Understanding the mechanistic details of product formation requires an understanding of the conformational preferences of this fundamental intermediate. Replacing the carbocation with borane (preserving π-accepting capabilities), ammonium (preserving positive charge), and methylene (preserving neither π-accepting capabilities nor charge) provides a systematic method to distinguish electrostatic and orbital effects on structure and internal stabilization. Several modes of internal stabilization—hyperconjugation, transannular π(alkene)···C(+) and transannular C-H···C(+) interactions—were uncovered, confirming and extending previous studies on this and similar systems.

Delocalization of charge and electron density in the humulyl cation—implications for terpene biosynthesis.

A range of oxoammonium salt-based oxidation reactions have been explored computationally using density functional theory (DFT), and the results have been correlated with experimentally derived trends in reactivity. Mechanistically, most reactions involve a formal hydride transfer from an activated C-H bond to the oxygen atom of the oxoammonium cation. Several new potential modes of reactivity have been uncovered and validated experimentally.

Article	Year
Oxidation of α-trifluoromethyl alcohols using a recyclable oxoammonium salt. The Journal of organic chemistry\| PubMed ID: 22931546	2012
Raman spectroscopy as a tool for monitoring mesoscale continuous-flow organic synthesis: Equipment interface and assessment in four medicinally-relevant reactions. Beilstein journal of organic chemistry\| PubMed ID: 24062851	2013
Oxoammonium salt oxidations of alcohols in the presence of pyridine bases. The Journal of organic chemistry\| PubMed ID: 24386938	2014
Methylenation of perfluoroalkyl ketones using a Peterson olefination approach. The Journal of organic chemistry\| PubMed ID: 24410210	2014
Delocalization of charge and electron density in the humulyl cation—implications for terpene biosynthesis. The Journal of organic chemistry\| PubMed ID: 25822613	2015
Toward a Unified Mechanism for Oxoammonium Salt-Mediated Oxidation Reactions: A Theoretical and Experimental Study Using a Hydride Transfer Model. The Journal of organic chemistry\| PubMed ID: 26167866	2015

Trevor A. Hamlin

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