Novel method for incorporating the CHF(2) group into organic molecules using BrF(3)

2-Alkyl-1,3-dithiane derivatives, easily made from alkyl bromides and the parent 1,3-dithiane, were reacted with BrF(3) to form the corresponding 1,1-difluoromethyl alkanes (RCHF(2)) in 60-75% yield. The reaction proceeds well with primary alkyl halides. The limiting step for secondary alkyl halides is the relatively low yield of the dithiane preparation. The two sulfur atoms of the dithiane are essential for the reaction.     

Reactions of 2,7-Dimethyloxepin with Dimethyldioxirane and Methyl(trifluoromethyl)dioxirane: Ring Opening and Probable Observation of the Intermediate “2,3-Epoxyoxepin”

The reactions of dimethyldioxirane (7) and methyl(trifluoromethyl)dioxirane (8) with 2,7-dimethyloxepin (4) both yielded Z,Z-3,5-octadiene-2,7-dione (Z,Z-6) as their initial stable products. This is the first published reaction of a dioxirane with an isolable pure oxepin. Reaction of the dienedione Z,Z-6 with one mole equivalent of either 7 or 8 yielded the corresponding monoepoxide. Treatment of this monoepoxide with another equivalent of 8 yielded the corresponding diepoxides (probably meso and R,S). The suggestion of Murray and co-workers that dioxiranes may model some of the reactivities of monooxygenases and their rapid epoxidations of alkenes under neutral conditions at low temperatures suggested their use. Our initial attempts to directly observe the putative intermediate 1,3-dimethyl-2,8-dioxabicyclo-[5.1.0]octa-3,5-diene (2,7-dimethyl-2,3-oxepin (2)] at low temperatures (ca. –60°C) yielded promising but inconclusive results when dimethyldioxirane (7) was employed. The epoxidation reaction was sufficiently slow that it only occurred measurably above –30°C, a temperature at which thermal ring opening to the dienedione is competitive. Initial reactions with the much more reactive methyl)trifluoromethyl)dioxirane (8) led to immediate ring opening at temperatures as low as –80°C. Since 8 is known to isomerize to methyl trifluoroacetate and since water is present, a trace of trifluoroacetic acid was suspected of catalyzing the ring opening of 2. Thus, inclusion of either suspended Na₂HPO₄ or miscible 2,6-di-t-butylpyridine at –80°C yielded an intermediate stable up to ca. 0°C, which is likely to be the 2,3-epoxyoxepin 2.     

Fast,very fast,and ultra-fast gas chromatography-mass spectrometry of thermally labile steroids,carbamates, and drugs in supersonic molecular beams

Gas chromatography-mass spectrometry (GC-MS) analyses of thermally labile compounds have been studied by using a short column fast gas chromatograph, coupled with fly-through electron ionization in supersonic molecular beams. Thirty-two compounds, which include steroids, carbamate pesticides, antibiotic drugs, and other pharmaceutical compounds, have been analyzed and the details of their GC-MS analysis are provided. The ability to analyze thermally labile compounds is discussed in relation to the speed of analysis. A new term, “speed enhancement factor” (SEF), is defined as the product of column length reduction and the carrier gas linear velocity increase, as compared with normal GC-MS conditions. Fast, very fast, and ultra-fast GC-MS are defined with a SEF in the ranges of 5–30, 30–400, and 400–4000, respectively. Trade-offs in the degree of dissociation, speed, gas chromatograph resolution, and sensitivity were studied and examined with thermally labile molecules. The experimental factors that affect the dissociation are described with emphasis on its reduction. We claim that the use of supersonic molecular beams for sampling and ionization provides the ultimate capability in the GC-MS of thermally labile compounds. The obtained 70-eV electron ionization mass spectra are shown, and an enhanced relative abundance of the molecular ion is demonstrated together with library search capability of these mass spectra, which is better than that reported with particle beam liquid chromatography-mass spectrometry. The performance of fast GC-MS in supersonic molecular beams is compared with other methods of fast GC-MS and with particle beam liquid chromatography-mass spectrometry.     

Benzannelated [9] and [13] annulenes: Formation,structural properties and the effect of benzannelation on the aromaticity of the (4n+2) π anionic sy

The synthesis of benzannelated [9] and [13] annulenenes is described, 1,2:3,4-dibenzocyclononatetraene 3 and its diphenyl derivative 10 show upon deprotonation the initial formation of a non-planar partially delocalized anions 4 and 11 respectively, which undergo into the planar aromatic-diatropic dibenzocyclononatetraenyl anions 4a and 12. The immediate formation of the aromatic 1,2:5,6 - dibenzocyclononatetraenyl anion 14 upon deprotonation of 1,2:5,6 - dibenzocyclononatetraene 13 precludes peri H-H repulsions in the aromaticity development of the dibenzocyclononatetraenyl anions. The deprotonation of tetrabenzo[13]annulene 15 afforded anion 17, which shows reduced diatropic character as compared with non-benzannelated[13] annulenyl anion. The spatial arrangement of 17 is discussed.     

Nitrogen and hydrogen as carrier and make-up gases for GC-MS with Cold EI

Gas chromatography–mass spectrometry (GC-MS) with Cold EI is based on interfacing GC and MS with a supersonic molecular beam (SMB) and sample compounds ionization with a fly-through ion source as vibrationally cold compounds in the SMB (hence the name Cold EI). We explored the use of nitrogen and hydrogen as carrier and make-up gases with Cold EI and found:

1. Nitrogen is very effective in cooling compounds in SMB and while helium requires 60 ml/min nitrogen provides effective cooling with only 7–8 ml/min combined column and make-up flow rate. Hydrogen is less effective than helium and requires higher flow rates.
2. The transition from helium to nitrogen (or hydrogen) is simple and fast and requires just closing the helium valve and opening the nitrogen valve.
3. The same column used with helium can be used with nitrogen or hydrogen.
4. The same elution times could be obtained with nitrogen or hydrogen as with helium.
5. The GC separation with nitrogen was reduced compared with helium and peak widths were increased by an average factor of 1.5 for similar elution times. Hydrogen provided ~0.7 narrower peak widths than helium.
6. The signal with nitrogen was reduced compared with helium by an average factor of 3.3 and the signal loss was reduced with higher compounds mass. With hydrogen the signal loss was about a factor of 1.5 but the baseline noise was higher thus with similar S/N as with nitrogen.
7. USEPA 8270 semivolatile mixture was easily analyzed with both nitrogen and hydrogen carrier gases.

     

From ketones, aldehydes or alkyl halides to terminal 1,1-difluoroolefins using BrF3

Terminal difluoromethylenes were prepared by two different routes: (a) by treating ketones and aldehydes with bis(methylthio)methane, producing 2-alkyl-1,1-bis(methylthio)alkene (2) (b) reacting alkyl halides with tris(methylthio)methane forming 1-alkyl-1,1,1-tris(methylthio)alkane derivatives (7). The reaction of either 2 or 7 with BrF₃, followed by oxidation with HOF·CH₃CN gave the difluorosulfonyl derivatives 4. Consecutive treatment with Zn led to the target difluoroolefins (5) in overall yields of 60-75%.     

General method for the preparation of beta,beta-difluoroacrylates using BrF3

Various esters were reacted with base, carbon disulfide, and methyl iodide, producing 2-carboalkoxy-1,1-bis(methyl sulfide)-1-alkenes (2). The reaction of 2 with BrF(3), followed by oxidation with HOF.CH(3)CN gave the bromodifluorosulfonyl derivatives 5. Subsequent treatment with Raney nickel led to alpha-substituted beta,beta-difluoroacrylates 6 in overall yields of 50-80%.     

Switch peptide via Staudinger reaction

A new transformation based on the Staudinger reaction is described, and its application in the design of a novel switch element to control peptide folding is demonstrated. We found that the azide switch is activated rapidly in water to promote acyl transfer using tris(2-carboxyethyl)phosphine hydrochloride (TCEP) via the Staudinger reaction. Our findings expand the repertoire of uses of the Staudinger reaction in chemical biology and the number of available triggers for use in switch peptides.