NovelFluorinated Carbanion Chemistry
Fluorinated carbanion reagents, such as CF3-, are reactive intermediates of great current interest because of their potential use in the synthesis of a large variety of trifluoro, difluoro, monofluoroalkyl and alkenyl substituted aliphatic and aromatic organic compounds having possible activity in pharmaceutical and agrochemical applications. There is particular interest in devising conditions where such reagents can be used for the purpose of stereoselective, “chiral” syntheses. Nevertheless the availability of useful reagents of these types has been limited due to their usual inherent chemical instabilities. Thus novel approaches have had to be devised to create effective “in situ” reagents that can perform these synthetic functions.
Our contribution to this area has been in the development of organic reducing agents, such as TDAE (see below), which function in conjunction with various fluorinated precursors, such as CF3I, RfI, ArC(O)CF2Br, and Het-CF2Br to generate a variety of in situ fluorinated carbanionic reagents that have proven to be highly effective in a large variety of nucleophilic reactions, such as those given in the example below for the trifluoromethyl anion.
Our current research in this area seeks to broaden the application of the reagents we have already discovered as well as to extend the chemistry to develop new fluorinated building block reagents.
The Diverse Application of a Novel Difluorocarbene Reagent to Fluoroorganic Synthesis
The interest in difluorocyclopropane compounds continues to grow because of the potential pharmaceutical, agrochemical and polymer applications of such materials. Virtually all difluorocyclopropane compounds are prepared via the addition of difluorocarbene to appropriate unsaturated organic compounds. Unfortunately difluorocarbene is the least reactive of the dihalocarbenes, and until the recent invention of our new difluorocarbene reagent, the ability to synthesize many types of difluorocyclopropanes was quite limited. This new reagent, trimethylsilyl 2-(fluorosulfonyl)-2,2-difluoroacetate (TFDA), has extended the scope of synthetic difluorocarbene chemistry tremendously. For example, until the invention of this reagent, it had not been possible to obtain decent yields of difluorocyclopropane products from α,β-unsaturated carbonyl compounds or even terminal alkenes. Other applications of this new difluorocarbene reagent are shown in the examples below, and work continues to discover new applications, particularly involving ylide chemistry and in the synthesis of polymers.
New Synthetic Challenges Involving the Pentafluorosulfanyl Group (SF5)
In 2002, while working to develop new high-density, high fluorine content materials for the Air Force, we discovered a new and convenient method for introduction of a pentafluorosulfanyl (SF5) group into functionalized aliphatic and aromatic compounds. Thus far largely ignored by pharmaceutical and agrochemical companies, probably because of the lack of convenient synthetic methodology, we consider the SF5 group a “substituent of the future”. It has virtually all of the attributes of the trifluoromethyl group, with some distinct advantages, being chemically more stable, inducing greater molecular lipophilicity, and being even more electron attracting.
By developing new an convenient methods using SF5Cl and SF5Br to make SF5-containing aliphatics and aromatics, we hope to stimulate greater research activity in this potentially important area of synthetic organic chemistry. Our own immediate emphasis in this area is to develop syntheses of presently unknown SF5-substituted heterocyclics, and to continue our efforts to develop new SF5-containing polymers.
Novel Synthetic Chemistry of Derivatives of Octafluoro[2.2]paracyclophane
Since the first isolation of the parent compound in 1949, interest in molecules containing the unique structural features of [2.2]paracyclophanes has never waned and has generated a literature filled with unusual structural features and chemistry. This chemistry includes their unique role as CVD precursors of what are known as Parylene polymers.
The totally bridge fluorinated [2.2]paracyclophane, a molecule we call AF4, only recently became generally accessible as a result of efforts from our lab. The presence of the bridge fluorines bestows this compound with novel properties and chemical behavior, some of which is exemplified in the examples below.
In addition to extending the synthetic aspects of AF4 chemistry to make new derivatives, some of which will have unusual molecular architecture, we will also be working to develop novel polymers from these materials.
Extraordinary Reactivity of Fluorinated Radicals
Over the last ten years we have been engaged in a very successful research program dedicated to obtaining a quantitative measure of the reactivity of radicals that contain fluorine. The results were always interesting, often surprising, and sometimes almost unbelievable, such as were the extraordinary reactivities of perfluoroalkyl radicals towards hydrogen abstraction from alkoxides (see below) or the huge kinetic isotope effects that were observed for H versus D abstraction from compounds like acetone (kH/kD = 17).
Our current interests in this area relate to studies of the reactivity of the SF5 radical, and to development of synthetic applications of the novel reactivities that we have discovered.