The highly stereoselective decarboxylation of (+)-1-bromo-1-chloro-2,2,2-trifluoropropanoic acid to give (+)-1-bromo-1-chloro-2,2,2-trifluoroethane [(+)-halothane] with retention of configuration

The absolute configuration of the title acid 2 has been determined to be S by X-ray crystallography. Thus, decarboxylation of 2 produces (S)-(+)-halothane with 99% retention of configuration. This behavior is compared to other stereoselective decarboxylation reactions of α-haloacids from the literature that also gave high degrees of retention of configuration when in the form of their quaternary ammonium salts, which contain one proton. The proton of the ammonium salt is necessary in order to protonate the anionic intermediate formed from decarboxylation. In the absence of this relatively acidic proton, we had previously found that using triethylene glycol (TEG) as both the solvent and proton source for the decarboxylation reaction of acid 2 caused poor stereoselectivity. This was in contrast to 1,2,2,2-tetrafluoro-1-methoxypropionic acid 6, which showed a high degree of retention of configuration in TEG. In order to rationalize this differing behavior, we report DFT studies at PCM-B3LYP/6-31++G⁷ level of theory (the results were additionally confirmed with 6-311++G⁷ and aug-cc-pVDZ basis sets). The energy barrier to inversion of configuration of the anionic reaction intermediate 11 of acid 2 is 10.23 kcal/mol. However, we find that the anionic intermediate 10 from acid 6 would rather undergo β-elimination instead of inversion of configuration. Thus the planar transition state required for inversion of configuration is never reached, regardless of the rate of proton transfer to the anion.     

Voice quality changes following phonatory-respiratory effort treatment (LSVT) versus respiratory effort treatment for individuals with Parkinson disease.

Perceptual ratings of hoarseness and breathiness were used to assess the efficacy of two intensive methods for treating dysarthrophonia in individuals with idiopathic Parkinson disease. One method emphasized phonatory-respiratory effort (the Lee Silverman Voice Treatment, LSVT) and the other emphasized respiratory effort alone (RET). Perceptual ratings were performed by two expert listeners based on random order presentation of the patients' pretreatment and posttreatment recordings of the "Rainbow Passage." The listeners were blinded to the patients and their treatment group. Statistically significant pretreatment to posttreatment improvement in hoarseness and breathiness was observed in the LSVT group but not in the RET group. The present findings are consistent with acoustic and physiologic findings reported previously, providing further evidence for the efficacy of the LSVT.     

The Parkinson larynx: Tremor and videostroboscopic findings

Patients with Parkinson's disease have a high incidence of speech, voice, and laryngeal abnormalities. To characterize laryngeal abnormalities, visual-perceptual ratings of endoscopic and stroboscopic examinations of 22 patients diagnosed with idiopathic Parkinson's disease and 7 patients with Parkinson's-plus syndromes were carried out by four trained viewers. Incidence of tremor, tremor location, phase closure, phase symmetry, amplitude, and mucosal waveform were scored. Tremor was observed in one or more of these conditions—rest, normal pitch and loudness, or loud phonation—for most of the 29 patients. Fifty-five percent of the idiopathic Parkinson's disease patients had tremor, with the primary location being vertical laryngeal tremor. Sixty-four percent of the Parkinson's-plus patients had tremor, with the arytenoid cartilages being the primary location. Laryngeal tremor was observed early in the disease in these Parkinson's disease patients. The most striking stroboscopic findings for the idiopathic Parkinson's disease patients were abnormal phase closure and phase asymmetry. Amplitude and mucosal wave-form were essentially within normal limits in the majority of the idiopathic Parkinson patients.     

Intensive voice treatment in parkinson disease: Laryngostroboscopic findings

As part of ongoing research to investigate and document the efficacy of intensive voice therapy to improve functional communication in patients with idiopathic Parkinson disease, 45 patients were enrolled in a controlled, randomized, prospective study. Pre- to posttreatment comparisons are presented here on 22 of those patients who underwent laryngeal imaging examination. Of the 22 patients, 13 patients received intensive therapy aimed at increasing vocal and respiratory effort (VR), whereas nine received intensive therapy aimed at increasing respiratory effort (R) only. All patients had a pretreatment evaluation that included two (but sometimes only one) voice recordings and an otolaryngologic examination with laryngostroboscopy. At the completion of 4 weeks of therapy (16 sessions), two voice recordings were made, and laryngostroboscopy was again performed. The pre- and posttherapy videolaryngostroboscopy tapes were then randomized and rated by four judges. Raters' findings were then compared with vocal intensity measured before and after therapy. The VR therapy group showed improvements on laryngostroboscopic variables: less glottal incompetence and no significant change in supraglottal hyperfunction after therapy. No differences were observed in the R-only group. The mean intensity increase in the VR therapy group was 12.5 dB, compared with a decrease of 1.9 dB in the R-only group. These findings suggest that in patients with Parkinson disease, intensive therapy focusing on phonatory effort improves adduction of the vocal folds as assessed by laryngostroboscopy. Differences in laryngeal function in these patients observed with fiberoptic laryngoscopy and rigid telescopic laryngoscopy are discussed.     

Selective free-radical dechlorination of 1,1-dichloro-2,2,2-trifluoroethyl difluoromethyl ether initiated thermally or by uv light: A practical and ‘green’ method for isoflurane synthesis

Treatment of 1,1-dichloro-2,2,2-trifluoroethyl difluoromethyl ether (3) with 2-propanol followed by either irradiation with UV light or heating with radical initiators gives the inhalational anesthetic isoflurane. Unlike most other common dechlorination methods, monoreduction is the exclusive process and the by-products acetone and HCl are relatively benign. Some comments about the mechanism of the reduction will be presented, along with solutions to problems encountered during scale-up.     

Regioselective alkylation reactions of 2,4-diphenyl-3H-1-benzazepine give either 3-alkyl-3H-1-benzazepines or 1-alkyl-1H-1-benzazepines

2,4-Diphenyl-3H-1-benzazepine is deprotonated with either LDA or KHMDS. The resulting anion is alkylated with alkyl halides or MeOTs, giving either products of alkylation at C3, or at N, or a mixture of both. The regioselectivity depends on the base, presence of the complexing agent HMPA, and the leaving group of the alkylating agent. Using MeI as alkylating agent gives exclusively the C3-methylated product, while using MeOTs gives exclusively the N-methylated product. The N-alkylated products show evidence of stereodynamic behavior in their NMR spectra.