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Background: ALK-positive advanced NSCLC patients treated with crizotinib typically progress after initial tumor response. However, most patients continue crizotinib beyond RECIST-defined Progressive disease (PD) if they are clinically benefiting from it. Methods: We screened 53 patients whose tumors harbor ALK rearrangement, and identified 32 patients received crizotinib as initial ALK inhibitor between 2010 and 2013. Baseline characteristics, response, sites of initial progression, efficacy of continuation therapy with crizotinib beyond PD, PFS, and OS were analyzed. Results: Among 32 patients who received crizotinib, 14 (43%) were male, median age was 43 (range: 21-66), 15 (47%) were never-smokers, 23 (72%) were stage IV at diagnosis. All patients had ECOG PS of 0/1 before treatment with crizotinib. Four patients without progression have received crizotinib. All 32 patients were radiologically evaluated. 21 patients achieved an objective response (65%): two patients had a complete response and 19 had a partial response. Disease control (ie, complete response, partial response, or stable disease) was achieved by 27 patients. Median PFS and OS were 168 days (range: 28-837) and 525 days (range: 45-1238), respectively. The most common sites of disease progression in these population were brain (n = 10), lung (n = 3), and bone (n = 3). Among 28 patients who had PD, 18 continued crizotinib treatment beyond PD, including ten patients with only isolated CNS metastasis, one with metastases in both the CNS and primary lesion, and seven with metastasis at non-CNS sites only. The patients who continued crizotinib beyond PD tend to be longer survival from the time of PD. Conclusion: Patients who continued treatment with crizotinib beyond PD were more likely to have isolated CNS metastasis. The present study suggested that continuation of treatment with crizotinib after PD may provide survival benefit to ALK positive patients.

Although patients of non-small cell lung cancer (NSCLC) with somatic activating mutations of the epidermal growth factor receptor (EGFR) gene dramatically respond to the EGFR tyrosine kinase inhibitors (EGFR-TKIs) treatment, the majority of them eventually undergo disease progression. Cigarette smoke is the strongest documented risk factor for the development of lung cancer. Nicotine, while not carcinogenic by itself, has been shown to induce proliferation, angiogenesis, and epithelial-mesenchymal transition in several experimental models; these effects can be associated with resistance to EGFR-TKI. In this study, PC-9 and 11_18 cell lines (EGFR-mutated NSCLC cell lines) were cultured with 1 µM nicotine for 1 month (designated as PC-9/N and 11_18/N cell lines, respectively). In vitro, these cell lines were resistant to EGFR-TKI, whereas short exposure of nicotine (1 week) had no influence on the sensitivity. Phosphorylation of EGFR in PC-9/N and 11_18/N cell lines were less decreased than the controls and high concentration of EGFR-TKI could decrease the phosphorylation. Higher expressions of nicotinic acetylchorine receptor α1 subunit were found in PC-9/N and 11_18/N cell lines than the cell lines with short nicotine exposure or the controls. Finally, we investigated 72 EGFR-mutated NSCLC patients indicating that the progression-free survival (PFS) time of 24 smoker patients was significantly reduced compared to those with never-smoker (median PFS; 6.7 versus 14.4 months, respectively, p = 0.013). Taken together, our findings indicate that chronic exposure of nicotine by cigarette smoke mediates resistance to EGFR-TKI via EGFR signal. The resistance can be overcome by high dose EGFR-TKI.

Background: Based on the mechanism of action and preclinical evidence to overcome EGFR-TKI resistance in EGFR mutant non-small cell lung cancer (NSCLC) cells by targeting survivin, a member of the inhibitor of apoptosis (IAP) family, a phase I study of YM155 (Y), a small-molecule selective survivin suppressant in combination with erlotinib (E) is being evaluated in patients with advanced NSCLC. Methods: Patients with previously EGFR-TKI treated refractory NSCLC received fix dose of E (150mg QD) in combination with escalating doses of Y (3.6, 4.8, 6.0 and 8.0 mg/m2) administered as a continuous intravenous infusion (CIVI) over 168 hours in 21-day treatment cycles. Biomarker analysis included changes of expression of survivin in biopsied tumor pre- and post Y administration detected by immunohistochemistry and survivin RT-PCR. Next generation sequencing (NGS), multiplex mutation screening and plasma cytokine analysis have also been conducted. Results: At the cutoff of March 7, 2014, a total of 10 patients received 35 cycles of Y at three different dose levels with standard doses of E. The most common adverse reactions judged to be related to Y was urine microalbuminuria. Grade 3 and 4 toxicities were rare. One patient receiving 4.8 mg/ m2/d Y developed a dose-limiting transient reversible grade 2 serum creatinine elevation. Clinical benefit was also observed in two patients; one patient who was previously treated by both EGFR-TKI and c-MET inhibitor in 3.6 mg/m2 dose cohort of Y experienced stable disease (SD) of > 36 weeks and the other patient who had progressed on 2 prior EGFR-TKI regimens was treated at 4.8 mg/m2 dose cohort of Y experienced SD with radiographic improvement of carcinomatous lymphangitis. PK and biomarker analysis are currently ongoing. Conclusion: Y up to 4.8 mg/m2/d administered in combination with standard dose of E every 3 weeks exhibited a favorable safety profile. Dose escalation is currently ongoing and updated results will be presented.

Background: S-1 granule is developed to meet the needs for patients, especially with dysphagia. The current study is the first phase I trial of S-1 granule to evaluate the safety, efficacy and pharmacokinetics of the combination with nedaplatin in patients with squamous cell carcinoma of the head and neck (SCCHN) Methods: Patients with advanced or refractory SCCHN were treated with i.v. nedaplatin at doses starting at 80 mg/m 2 (level 1) and escalating to 90 mg/m 2 (level 2), and S-1 granule at a fixed daily oral dose of 80 mg/m 2 on days 1 to 14 every 3 weeks. The primary end-point was to determine the recommended dose for nedaplatin given in combination with a fixed dose of S-1 granule. Results: Twenty patients (median age, 63 yr) were enrolled in this study. One of the first six patients at dose level 1 and all three patients at dose level 2 experienced a dose limiting toxicity (the delay of >2 weeks in administering the second treatment cycle in one and two patients at dose level 1 and 2, respectively. grade 4 thrombocytopenia in one patients at dose level 2. The recommended dose was thus determined as level 1, and an additional 11 patients were assigned this level. The most frequent toxicities were leucopenia, neutropenia, thrombocytopenia, fatigue, and anorexia. All observed adverse events were well managed and no treatment-related death occurred. The response rate was 42.1% (8 of 19 patients), and the median progression-free and overall survival time was 5.5 and 12.0 months, respectively. Pharmacokinetic parameters of S-1 granule did not appear to differ substantially from those obtained previously for S-1 capsule and no pharmacokinetic interaction between S-1 granule and nedaplatin was detected. Conclusions: The combination of S-1 granule and nedaplatin is well tolerated and appears to potentially possess activity in HNSCC.

Publisher Summary This chapter deals with the ionic dissociation of carbon–carbon σ bonds in hydrocarbons and the formation of authentic hydrocarbon salts. Carbon compounds are most commonly constructed using covalent bonds, and the nature of the bond is of prime importance in all organic compounds. Among the compounds of carbon, hydrocarbons, which are made up of only hydrogen and carbon, are the simplest known group of organic compounds having exclusively covalent bonds. The search for such novel hydrocarbons depends primarily on the synthesis and examination of highly stabilized hydrocarbon cations and anions. The details of structural features such as the length of the carbon–carbon bond σ that easily undergoes heterolysis and the spatial arrangement of ions in hydrocarbon salts are intriguing subjects. Electrical characterization of the hydrocarbon salts, though they are not stable enough to air and light, might be useful as new functional materials.

Background The prognosis of gastric cancer with peritoneal metastasis is extremely poor. Neither systemic chemotherapy nor surgery alone prolongs survival of patients significantly. Methods Patients diagnosed with advanced gastric cancer underwent staging laparoscopy and received chemotherapy when peritoneal dissemination and/or cancer cells on peritoneal cytology were confirmed. The chemotherapy regimen consisted of S-1, weekly intravenous and intraperitoneal paclitaxel, which was verified in our phase II trial (Ann Oncol 2009). S-1 was administered at 80 mg/m2/day for 14 consecutive days, followed by 7 days rest. Paclitaxel was administered intravenously at 50 mg/m2 and intraperitoneally at 20 mg/m2 on days 1 and 8. Clinical response of chemotherapy was assessed by computed tomography, gastroendoscopy, peritoneal cytology and second-look laparoscopy. Radical gastrectomy was carried out when macroscopic curative resection was made achievable by chemotherapy. Chemotherapy was restarted after operation as soon as possible. Overall survival, relapse free survival, morbidity and mortality of gastrectomy were evaluated. Results Out of 100 patients with peritoneal metastasis who received chemotherapy, 60 patients underwent gastrectomy after response to chemotherapy, including 54 with macroscopic metastasis and 6 with positive peritoneal cytology only. A median of three courses were administered preoperatively (range 1–16). Total or distal gastrectomy with lymphnode dissection was carried out in 54 or 6 patients, respectively. The median survival time was 34.5 months. The median relapse-free survival was 16.7 months. The first site of relapse was the peritoneum in 24 patients and the other organ site in 17 patients. Postoperative complications included anastomotic leakage and pancreatic fistula in two patients each, which were healed conservatively. There were no treatment-related deaths. Conclusions Gastrectomy combined with S-1, intravenous and intraperitoneal paclitaxel is safe and active for gastric cancer patients with peritoneal metastasis.

SRPX2 (Sushi repeat-containing protein, X-linked 2) has recently emerged as a multifunctional protein that is involved in seizure disorders, angiogenesis and cellular adhesion. Here, we analyzed this protein biochemically. SRPX2 protein was secreted with a highly post-translational modification. Chondroitinase ABC treatment completely decreased the molecular mass of purified SRPX2 protein to its predicted size, whereas heparitinase, keratanase and hyaluroinidase did not. Secreted SRPX2 protein was also detected using an anti-chondroitin sulfate antibody. These results indicate that SRPX2 is a novel chondroitin sulfate proteoglycan (CSPG). Furthermore, a binding assay revealed that hepatocyte growth factor dose-dependently binds to SRPX2 protein, and a ligand–glycosaminoglycans interaction was speculated to be likely in proteoglycans. Regarding its molecular architecture, SRPX2 has sushi repeat modules similar to four other CSPGs/lecticans; however, the molecular architecture of SRPX2 seems to be quite different from that of the lecticans. Taken together, we found that SRPX2 is a novel CSPG that is overexpressed in gastrointestinal cancer cells. Our findings provide key glycobiological insight into SRPX2 in cancer cells and demonstrate that SRPX2 is a new member of the cancer-related proteoglycan family.

Loss of PTEN (phosphatase and tensin homolog) was recently shown to contribute to resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in EGFR mutation-positive non-small-cell lung cancer (NSCLC) through activation of the protein kinase AKT. We previously showed that down-regulation of the expression of the antiapoptotic protein survivin by EGFR-TKIs contributes to EGFR-TKI-induced apoptosis in EGFR mutation-positive NSCLC cells. We have now investigated the role of survivin expression in EGFR-TKI resistance induced by PTEN loss. The EGFR-TKI erlotinib did not affect survivin expression or induce apoptosis in EGFR mutation-positive NSCLC cells with PTEN loss. Down-regulation of survivin either by transfection with a specific siRNA or by exposure to the small-molecule survivin suppressor YM155 reversed erlotinib resistance in such cells in vitro. Furthermore, combination therapy with YM155 and erlotinib inhibited the growth of tumors formed by EGFR mutation-positive, PTEN-deficient NSCLC cells in nude mice to a greater extent than did treatment with either drug alone. These results thus indicate that persistent activation of signaling by the AKT-survivin pathway induced by PTEN loss underlies a mechanism of resistance to erlotinib-induced apoptosis in EGFR mutation-positive NSCLC. They further suggest that the targeting of survivin has the potential to overcome EGFR-TKI resistance in EGFR mutation-positive NSCLC.

Purpose Neuropathic pain frequently occurs in cancer patients, but the mechanism has yet to be clarified and no drug therapy has been established. The purpose of this study was to investigate the effect of duloxetine on neuropathic pain in cancer patients. Methods The subjects were 15 cancer patients (9 males) with neuropathic pain who visited the Kinki University Faculty of Medicine Hospital between April 2011 and October 2011 and met the IASP diagnostic criteria for neuropathic pain. Duloxetine was administered in patients in whom pregabalin could not be administered, was ineffective, or was effective but the dose could not be elevated due to an adverse effect. The influence of duloxetine on pain and adverse effects was investigated retrospectively. Results Pain was reduced in 7 of the 15 patients. Sleepiness and a light-headed feeling were improved in three in whom pain was not reduced. Thus, the duloxetine was judged to be effective in 10 patients. The maintenance dose of duloxetine was 20–40 mg/day in patients who took the drug for 2 weeks or longer. Conclusion Duloxetine administration may be effective for neuropathic pain in cancer patients who cannot tolerate pregabalin administration.

2,2-Dimethyl-1-(p-methoxyphenyl)propyl cation has been generated by treatment of the corresponding chloride with AgSbF6 in SO2–CH2Cl2(20% CD2Cl2) at –98 °C and its 13C NMR spectrum observed. The reactions of the generated carbocation with methanol or phenol give products with a rearranged carbon atom skeleton and non-rearranged products with complete racemization, as expected for a typical carbocation reaction, whereas the solvolysis of the corresponding p-nitrobenzoate in phenol affords exclusively the non-rearranged products with partial retention of configuration. Such distinctions between generated carbocation reactions and the solvolysis reactions indicate that no dissociated (free) carbocation intermediate intervenes even in this solvolysis system, i.e., it is one of a few systems which have been hitherto confirmed to proceed via multiple intermediate stages.

The relative rates and regioselectivities were determined for the reaction of unsubstituted and substituted tropylium ions containing methoxy, methylthio, methyl, phenyl, methoxycarbonyl or cyano with borohydride ion in acetonitrile at 25°C. The rate increases in the order methoxy- < methylthio- < methyl- < unsubstituted-, but it levels off for unsubstituted-, phenyl-, methoxycarbonyl- and cyano-tropylium ions. From the lower limit of the rate constant of the methoxytropylium ion, which was estimated by the stopped-flow technique, and the logarithmic plot of the relative rates against those of the one-electron reduction of the tropylium ions with Cr(II) ion, the reaction with the borohydride ion at the level-off region was concluded to be diffusion-controlled. In spite of the diffusion-controlled behavior, these tropylium ions show regioselectivities. The data indicate that the present cation—anion combination reaction is not a one-step reaction, but proceeds via a cation—anion encounter-pair (or charge-transfer) intermediate, providing a clear example of the presence of intramolecular selectivity in the absence of intermolecular selectivity. CNDO/2 SCF MO calculations suggest that the regioselectivity is primarily frontier orbital controlled.

The 13 C NMR spectra for all seventeen methylated tropylium ions have been obtained in acetonitrile- d 3 and the chemical shifts of the Me- and the ring-carbons assigned. The plots of the 13 C shifts of ring-carbons against charge densities calculated by the simple Huckel MO method by the use of the inductive and the heteroatom models afford linear correlations. The 13 C shifts for the Me-carbons and the 1 H shifts for the Me- and the ring-hydrogens are linearly correlated with the 13 C shifts for the ring-carbons to which they are attached, provided the Me groups or the ring-hydrogens residing in similar steric environments are compared. From the slopes of the correlation lines the dependences of the 13 C shifts of Me-carbons and the 1 H shifts of ring and Me-hydrogens on charge densities of ring-carbons have been estimated to be 35–50, 11–16, and 2.9–5.1 ppm, respectively, by assuming 160 ppm for the charge dependence of the 13 C shifts of the ring-carbons.

8 Phenyl- ( 2 ) and 8,8 diphenyl-heptafulvenes ( 3 ) have been synthesized and fully characterized. The 220 MHz NMR data on 2 and 3 , as well as the 13C NMR data on 3 , indicates only a small contribution of the dipolar structure for this system. The electrophilic and nucleophilic reagents react at different sites of this system while protonation of 2 and 3 occurs at the exocyclic methylene carbon butylation occurs at the 7 -membered ring, i.e. the 1- and 3-positions of 2 and only at the 3-position of 3 , when treated with n-BuLi. Cycloaddition with tetracyanoethylene gives the [8 + 2]-cycloadduct for 2 and the [4 + 2] adduct for 3 .

A series of polymethylenebis(diphenylcyclopropenium) dications with the polymethylene chain of one to six carbons (4n=1–6) were synthesized and characterized by spectral and analytical means. Among the dications 4n=3–6 which were isolated as perchlorates, 4n=3 was shown by the pKR+ measurements to be destabilized by 1.3 pK units as compared with 4n=4–6. The values of reduction potential exhibited the same tendency. The chromium(II) ion reduction of 4n=6, a representative dication, afforded a polymeric material containing a hexylbenzene unit. The dication 4n=2 was isolable only as a complex salt with SbCl6− and Cl−: the conventional hydride abstraction from 1,2-dicyclopropenylethane using trityl perchlorate resulted in rearrangements affording 4,9,10-triphenylphenanthrene and the unknown monocation C32H25+ containing the tropylium ring. A possible mechanism for these rearrangements is presented. On the other hand, the dication 4n=1 was observable only in a highly acidic solution due to the ready deprotonat...

A series of substituted phenyltropylium (I) and n-alkyltropylium ions (II) has been synthesized, and the kinetic measurements for the one-electron reduction of these ions have been carried out with Cr(II) in 10% HCl at 25°C. A linear correlation is observed between the logk2 values, for I (X-C6H4-C7H6+, X=p-OH, p-OCH3, p-CH3, H, p-Cl, p-Br, p-CN, m-OCH3) and for II (CnH2n+1-C7H6+, n=0,1–6), and the transition energy of the charge-transfer band of these ions, with pyrene as a donor. In addition, the values of logk2 for I exhibit a good linear free-energy relationship with pKR+ and also with the σ -value (ρ=+1.31), but not with σ+. The n-alkyl group is shown to diminish the reducibility of the tropylium ion, and a slight alternation effect of the length of the n-alkyl chain on the K2’s is observed.

Solvolysis of threo-2-(p-methoxyphenyl)-1-methylpropyl brosylate (1) and its deuterium derivative (1-2-d) has been carried out in N,N-dimethylacetamide (DMA) as solvent at 50.0 and 75.0 °C. Product examination revealed that in the presence of water (0.17 mol/dm3) the main product is threo-2-(p-methoxyphenyl)-1-methylpropyl acetate (73% at 50 °C), but in the absence of water (Z)-2-(p-methoxyphenyl)-2-butene (5) (ca. 70% at 50 °C). Both of these products are derived from a threo-imidatonium ion [threo-R-Amide]+ which is produced by DMA capture of the tight ion-pair [R+OBs−] (2) from the front-side. A part (ca. 14% yield) of the (Z)-olefin 5 is directly led from the tight ion-pair 2. The formation of the olefin 5 can not be explained by intervention of the phenyl-bridged ion. Although the rate of the brosylate 1 exhibits the kΔ portion deviating upwards from the Hammett plot for a series of threo-2-aryl-1-methylpropyl brosylates, the Schleyer’s kΔ-ks treatment for the rate-(retained)product correlation was u...

Correlated rotation of the cycloalkyl groups has been observed by 13C NMR for the title compounds containing six-, seven-, or eight-membered rings. The ΔH≠ value increases with the increase in the ring size, attaining 79.5 ± 2.1 kJ mol−1 when all the three rings are eight-membered. Molecular mechanics calculations indicated that the magnitude of internal angles is a major contributing factor.

The one-electron reduction of a series of phenyl- and/or n-propyl-substituted cyclopropenium ions with Cr(II) has been carried out in a 10% HCl solution. The reduction of triphenylcyclopropenium (Ia), diphenyl-n-propylcyclopropenium (Ib), and phenyldi-n-propylcyclopropenium (Ic) ions quantitatively gives dimers of the respective cyclopropenyl radicals, i.e., the bis(cyclopropenyl) derivatives, whereas the tri-n-propylcyclopropenium ion (Id) is quite unreactive. A kinetic study has shown that the reactivity of these stable carbonium ions toward the one-electron reductant (Cr(II)) is lowered with a decrease in the number of the phenyl substituent: k225°C=3.0×10−4l/g-ion·s for Ia, 2.7×10−6l/g-ion·s for Ib, 2.8×10−9l/g-ion·s for Ic, and

Introduction of a t-butyl group to the 2- or 3-position of 7-cyanocycloheptatriene facilitates the observation of the two conformers by 1H and 13C NMR at low temperatures. The chemical shift of equatorial H(7) and the equilibrium constant for the ring inversion with respect to 7-cyanocycloheptatriene have been reexamined and corrected.

Electrophilic or hydrogen bonding assistance of hydroxylic molecules can be verified by the rate acceleration in SN1 acetolysis of 1-phenylethyl chloride, by retentive outcomes of the substitution products in the reaction of an optically active trifluoroacetate in benzene, and by kinetic partial resolution of 1-phenylethyl chloride in optically active carboxylic acid solvents. Nucleophilic solvation of carbocation intermediates is another driving force for SN1 ionization and can be verified by rear-side shielding of the intermediate by nitriles and hindered phenols in the solvolyses in these solvents. As a solvolysis solvent, phenol has an amphiphilic, electroand nucleo-philic, driving force, which has been proved by stereochemical outcomes of phenolyses of 1-phenylethyl systems with vanous leaving groups and by those of competitive methanolysis and phenolysis of optically active 1-phenylethyl chloride. There are two types of phenolysis pathways for simple alkyl and aralkyl systems; both of them afford retained phenyl ether from optically active substrate in the presence of a base. One type has single ionpair intermediate, while the other has two. In the latter most of the phenolysis products are derived from the second intermediate. The number of intermediates has been determined by use of Winstein's kp-kt plot against concentration of added salt, such as LiOPh, NaOPh, 2,6-di-tert-butyl-4-methylpynidinium phenoxide, LiC1O4, and Bu4NC1O4. Examination of the stenic outcomes of three products, ROPh, 0and pRC6H4OH, suggests a variety of ion-pair structures, including four-center quadrupole and rear-side shielded ion-pair, as the first and second intermediates, respectively, in phenolyses. The usefulness of the methanol perturbation method for examination of the intermediate structure has been elucidated in the retentive phenolysis of l-p-anisyl-2,2-dimethylpropyl p-nitrobenzoate. INTRODUCTION The intermediacy of the carbocation in the solvolyses of alkyl and anal kyl halides was suggested in the mid 1920's (Ref. 1). Ten years later the mechanism was designated as SN1 by Ingold, and a free carbocation was suggested as the intermediate (Ref. 2). In 1940 the role of solvent molecules in carbocation formation was first described by Hammett, and the reaction was depicted as polymolecular solvolysis (Ref. 3). He pointed out the inipient solvation of the leaving group ion in the transition state as the driving force of the solvolytic reaction. Eighteen years later Winstein presented irrefutable experimental evidence for two kinetically distinguishable ion-pairs as the successive intermediates (Ref. 4), and since then the ionpairing and ion-pair return has been shown to be of critical importance in every solvolysis. Although many experimental methods have been designed and refined, they have mostly been used to add detailed and additional examples to Winstein's mechanistic scheme, and mechanistic interpretation of solvolytic displacement has not changed much in principle. Reviews of some of the developments have recently been published (Ref. 5). Despite such a long history some problems of importance still remain, mainly because of the experimental difficulty of direct observation of carbocation intermediates with a very short life in a very low concentration. Hence microscopic features of ionization, especially, the role of solvent molecule as an electrophilic (electron-accepting) and a nucleophilic (electron-donating) molecule have not been entirely disclosed. The structure of ion-pair intermediates has also been a subject for debate, although Winstein's intimate and solvent-separated ion-pair theory has prevailed. In addition, the molecularity of solvent in connection with "borderline case" solvolysis is still open for future study (Ref. 6). Phenol has remained relatively unfamiliar among the traditional solvolysis solvents. However, it has high ionizing power (vide infra) and low polarity, and has three reaction centers towards the carbocation intermediate. In addition, phenolysis generally gives the phenyl ether with predominantly retained configuration, starting from optically active substrates which do

The salt effect of (n-Bu)4NClO4 and NaOPh on the polarimetric and titrimetric rate constants (kp and kt, respectively) has been examined for the SN1 solvolyses of optically active 2,2-dimethyl-1-(p-methoxyphenyl)propyl (1) and 2,2-dimethyl-1-phenylpropyl p-nitrobenzoates (2) in pure phenol solvent. Four patterns, A, B, C, and D of the kp–kt profile against the added salt concentration have been observed for the phenolyses of 1, 2, and 2,2-dimethyl-1-(p-nitrophenyl)propyl p-nitrobenzoate (3). The patterns can specify the number of the sequential ion-pair intermediates (i.e., one or two), the product-forming stage (i.e., the 1st or the 2nd intermediate), and the species of reactant at the product-forming step (i.e., solvent phenol molecule, the phenoxide, or the perchlorate). The feature of the pattern of the kp–kt profile is predominantly controlled by two factors, (i) the stability of the carbocation intermediate derived from the substrates 1–3 and (ii) the nucleophilicity of the added salt. The patterns ...

Solvolysis of a series of ring substituted threo-1-methyl-2-phenylpropyl brosylates has been carried out in N,N-dimethylacetamide (DMA) as solvent. Hammett treatment of the rate data indicated that the DMA solvolysis of the unsubstituted brosylate (1c) falls into the category of ks pathway (100%). In order to gain further information of the nature of the ks pathway, the DMA solvolysis of 1c or 1c-2-d (labeled at C(2)) has been conducted. The product distribution, effect of water content on it, the composition and deuterium distribution of recovered brosylate, kinetic isotope effect, and the deuterium distribution of product have been investigated. The products consisted of the olefins ((E)- and (Z)-2-pheny1-2-butenes, and 2- and 3-phenyl-1-butenes), and, in the presence of water in DMA, the carboxylates (erythro- and thero-1-methyl-2-phenylpropyl acetates) and the small amount of diastereomeric alcohols. The major product was (Z)-2-phenyl-2-butene, indicating the occurrence of anti-E1 process. The deuteri...

The reaction of trichlorocyclopropenium tetrachloroaluminate with cyclopropylbenzene has been found to readily afford the disubstitution products, bis(p-cyclopropylphenyl)- (1a), (p-cyclopropylphenyl) (o-cyclopropylphenyl)-, and bis(o-cyclopropylphenyl)cyclopropenones, each of which has been separated and fully characterized spectroscopically. The tris(p-cyclopropylphenyl)cyclopropenium ion (2) could not be obtained by the direct trisubstitution of the trichlorocyclopropenium ion with cyclopropylbenzene, but has been synthesized via two other routes starting from cyclopropenone 1a. The UV and 13C NMR spectral data of the cation 2 indicated the conjugative interaction of the para-cyclopropyl group with the cyclopropenium ring. However, the cation-stabilizing effect of the para-cyclopropyl group, as shown by the pKR+ value (3.23 in 23% ethanol) for 2, is much smaller than in the case of the tris(p-cyclopropylphenyl)methyl cation. This has been interpreted in terms of the decrease in delocalization of the po...

The carbonylation of the l-adamantyl cation with carbon monoxide in carbon tetrachloride at atmospheric pressure in the presence of trifluo-romethanesulfonic acid (triflic acid) and adamantane affords 3-hydroxy-4-homoadamantyl l-adamantanecarboxylate ( 2 ) in 70% yield under appropriate conditions. Among various l-adamantyl cation precursors tested, l-adamantyl trifluoromethanesulfonate (triflate) and methanesulfonate (mesylate) have given the best, comparable results. As to the acid catalyst, fluorosulfonic acid is less effective than triflic acid, and 100% sulfuric acid and methanesulfonic acid are completely ineffective to produce 2 . It is recommended to use five mol each of triflic acid and adamantane per mol of l-adamantyl mesylate or triflate. This reaction proceeds via the addition of the l-adamantanecarbonyl cation to l-adamantanecarbaldehyde, a transient intermediate, followed by the Wagner-Meerwein rearrangement. The hydroxy ester 2 is easily converted into 3,4-homoadamantanediol which is a promising starting material for 3,4-bifunctional homoadamantane derivatives.

Technetium-99m-diethylene-triamine-penta-acetic acid (DTPA) and 111In-DTPA were injected simultaneously into 21 patients with various levels of renal function. Scintiphoto, camera data renograms and clearance values (plasma sampling) were obtained for each patient. The mixed isotope scintiphoto images were of intermediate quality and the images with 111In-DTPA were apparently inferior to those with 99mTc-DTPA. These equations were obtained: (1) y = 0.30 + 0.91 x (coefficient of correlation r = 0.98) where x is the value at T peak (time of maximum count on renogram) obtained with 99mTc-DTPA and where y is the value at T peak with 111In-DTPA. (2) y = -0.09 + 1.006 x (r = 0.99) where x is the value at T3/4 (time interval between the time of maximum count to the time of 3/4 of maximum count on renogram) and where y is the value at T3/4 obtained with 111In-DTPA. (3) y = -0.01 + 1.007 x (r = 0.98) where the x and y values were for the excretion ratios (counts at 20 min/maximum counts on renogram). (4) y = 0.81 + 0.98 x (r = 0.99) where x and y are the clearance values.

13 C NMR studies showed that the population of the norcaradiene form of the title systems containing p-CH 3 O, H, and p-CF 3 on the 7-aryl group increases in this order. The result is consistent with the prediction from the π-acceptor strength of the aryl group estimated by INDO calculations.

endo-2-Phenyl-endo-6-tropyliobicyclo[2.2.2]octane 2 exhibits intramolecular charge-transfer (CT) interaction, but rearranges to exo-6-tropylio isomer 3 in acetonitrile with the 2/3 ratio of ca.0.07 at equilibrium. This ratio indicates that the steric repulsion between the face-to-face phenyl and tropylium rings at ca.2.5A is estimated to be at least ca.1.6kcal/mol.

The effect of added aniline on the polarimetric (kp) and titrimetric rate constants (kt) has been reexamined for the phenolysis of 1-phenylethyl chloride (RCl) in phenol–benzene (1:1 w/w). The kp–kt plot against the aniline concentrations exhibited the pattern C, instead of A which was the previous results in our laboratory. It has been revealed that the previous rate constants at the lower aniline concentrations, including the case of absence of aniline, were underestimated due to overlooking the reverse reaction caused by the liberated hydrogen chloride. The pattern C indicates that the first ion pair intermediate, not the second one, is nucleophilically attacked by solvent phenol molecule. The major products were the partially retained o-RC6H4OH, the partially inverted p-RC6H4OH, together with the partially retained ROPh. The same kp–kt pattern C has been observed for the competitive solvolysis of RCl in phenol–methanol (85:15 w/w), which produced the partially retained ROMe and ROPh, the partially inv...

The existence of a linear free-energy relationship between the phenolic reactivity and the selectivity for attack of the phenol molecule on carbonium ion intermediates has been established for the titled substrates. The examples are the first ones for the reaction between the carbonium ions and an ambident molecule.

Synthesis, properties, and the result of one-electron reduction are described for the title compound, which is the first example of the stable dication containing two cationic rings in a close face-to-face arrangement.

The cycloheptatriene (CHT)–norcaradiene (NCD) equilibria of eight 7-aryl-2,5-di-t-butylcyclohepta-1,3,5-trienes in CS2–CD2Cl2 have been studied with the use of variable-temperature 13C n.m.r. The equilibrium constants (K=[NCD]/[CHT]) below the coalescence temperatures were calculated from signal intensities; those at higher temperatures were obtained by use of the equation K=(δCHT–δ)/(δ–δNCD). The enthalpy (ΔHo) for the conversion of the CHT into the NCD tautomer decreases in the substituent order p-MeO > p-Me > H > p-Br ∼p-Cl > m-Cl > p-CF3 > m,m′-Cl2, with the ΔHo values for p-MeO and m,m′-Cl2 2.64 ± 0.11 and –0.81 ± 0.13 kJ mol–1, respectively. The ΔHo values are linearly correlated not only with the Hammett σ-constants, but also with the π-acceptor ability (the D value) of the aryl carbon atom adjacent to C(7) as estimated by INDO calculations; this supports Hoffmann and Gunther's donor–acceptor theory. The 13C signals of C(3) and C(4) in both the NCD and the CHT tautomer undergo downfield shifts as the D value of the aryl group increases; the shift of the former is 4.3 times more sensitive than that of the latter as evaluated by the Hammett plot. In addition, the difference in the 13C shift of the para-carbon atom between the NCD and the CHT tautomer is larger in the 7-(m,m′-dichlorophenyl) than in the 7-phenyl system. These results suggest that conjugative interaction between the cyclopropane ring in the NCD structure and the aryl group increases with increase in the π-acceptor ability of the aryl group.

Solvolysis of 7β-methylbicyclo[3.3.1]non-3β-yl tosylate (1) was carried out in a series of carboxamides, N-methylformamide (NMF), N-methylacetamide (NMA), N,N-dimethylformamide (DMF), and N,N-dimethyl-acetamide (DMA), as solvents. The rate (k1 first-order rate constant) of 1 decreases in the order NMF>NMA>DMF>DMA, a linear free-energy relationship being found between the rates of 1 and those of 1-adamantyl tosylate in acetic acid and 80% ethanol as well as the carboxamides. The products consist of olefin (≥96%) (exo-7-methylbicyclo[3.3.1]non-2-ene (4) and 3-methylbicyclo[3.3.1]non-2-ene (5)) and small amounts of esters (acetates or formates, ≤4%). The content of rearranged olefin 5 is considerably less than that of acetolysis (55%) and ethanolysis (55%), decreasing in the order NMF (34%)>NMA(22%)>DMF(13%)>DMA(9%). A linear reactivity-selectivity relationship holds between log k1 and log (%5/%4) for the four carboxamide solvents. The observed kinetic isotope effect (kH/kD=1.01±0.03) for 7α-deuterium-tagged...

A novel non-benzenoid aromatic cation, tricyclopropylcyclopropenium ion, was synthesized by smooth addition of photochemically generated cyclopropylchlorocarbene to dicyclopropylacetylene, and was shown to have remarkable stability.

The 1H NMR study showed that the endo-cyano isomer of the title compound is slightly more stable than the exo-cyano isomer with a population ratio of 22:17 at −120°C. In the cycloheptatriene form, the axial-cyano conformer is much less stable than the equatorial counterpart with a ratio of 1.7:59. The results can account for the marked stabilization in syn-11-cyanotricyclo[4.4.1.0]undeca-2,4-diene by the syn-cyano group.