Formation and Mechanism for Reactions of Ring-Substituted Phenonium Ions in Aqueous Solution.

The results of studies on the structure and reactivity of spiro[5.2]oct-5,7-diene-4yl carbocation [phenonium ion] have had a significant impact on the course of discussion about the distinction between classical and nonclassical carbocations. This minireview will present a brief overview of the structure, bonding and reactivity of ring substituted phenonium ions (X-4+), with an emphasis on work completed since 2004. The discussion will focus on the development of new experimental protocol for determination of the selectivity for addition of nucleophilic anions to X-4+ in aqueous solution. The existing relationships between carbocation lifetime and nucleophilic selectivity, and the known lifetime of ca 140 sec for spiro[2.5]oct-4,7-diene-6-one provide rough estimates of the lifetimes for 4-Me-X-4+ and 4-MeO-X-4+ in aqueous solution. Evidence is presented that nucleophile addition to X-4+ proceeds through an "exploded" transition state, with relatively weak bonding the nucleophile and leaving group, and the development of significant positive charge at the reacting primary cyclopropyl carbon.

Risk Factors for Prolonged Treatment of Whiplash-Associated Disorders.

OBJECTIVES: Whiplash-associated disorders (WAD) are the most common injuries that are associated with car collisions in Japan and many Western countries. However, there is no clear evidence regarding the potential risk factors for poor recovery from WAD. Therefore, we used an online survey of the Japanese population to examine the association between potential risk factors and the persistence of symptoms in individuals with WAD. MATERIALS AND METHODS: An online survey was completed by 127,956 participants, including 4,164 participants who had been involved in a traffic collision. A random sample of the collision participants (n = 1,698) were provided with a secondary questionnaire. From among the 974 (57.4%) respondents to the secondary questionnaire, we selected 183 cases (intractable neck pain that was treated over a period of 6 months) and 333 controls (minor neck pain that was treated within 3 months). Multivariable logistic regression analysis was used to evaluate the potential risk factors for prolonged treatment of WAD. RESULTS: Female sex, the severity of the collision, poor expectations of recovery, victim mentality, dizziness, numbness or pain in the arms, and lower back pain were associated with a poor recovery from WAD. CONCLUSIONS: In the present study, the baseline symptoms (dizziness, numbness or pain in the arms, and lower back pain) had the strongest associations with prolonged treatment for WAD, although the psychological and behavioral factors were also important. These risk factors should be considered when evaluating patients who may have the potential for poor outcomes.

Swain-Scott Relationships for Nucleophile Addition to Ring-Substituted Phenonium Ions.

The products of the reactions of 2-(4-methoxyphenyl)ethyl tosylate (MeO-1-Ts) and 2-(4-methyphenyl)ethyl tosylate (Me-1-Ts) with nucleophilic anions were determined for reactions in 50/50 (v/v) trifluoroethanol/water at 25°C. In many cases the nucleophile selectivity kNu/ks (M-1) for reactions of nucleophile and solvent, calculated from the ratio of product yields, depends upon [Nu-]. This demonstrates the existence of competing reaction pathways, which show different selectivities for reactions with nucleophiles. A carbon-13 NMR analysis of the products of the reactions of substrate enriched with carbon-13 at the α-carbon, X-1-[α-13C]Ts, (X = -OCH3, -Me) with nucleophilic anions in 50/50 (v/v) trifluoroethanol/water at 25°C shows the formation of X-1-[ß-13C]OH, X-1-[ß-13C]OCH2CF3 and X-1-[ß-13C]Nu (Nu = Br, Cl, CH3CO2, Cl2CHCO2) from the trapping of symmetrical 4-substituted phenonium ion reaction intermediates X-2+ . The observation of excess label in the α-position, [α-13C]/[ß-13C] > 1.0, for both the water and nucleophile adducts, shows that water and anionic nucleophiles also react by direct substitution at X-1-[α-13C]Ts. The ratios of product yields, [α-13C]/[ß-13C], and observed nucleophile selectivity (kNu/ks)obs were used to dissect the contribution of direct nucleophile addition at Me-1-Ts and trapping of X-2+ to the product yields. The product yields from partitioning of the intermediate gave the nucleophile selectivity kNu/ks (M-1) for X-2+ . Swain-Scott plots of log (kNu/ks) are correlated by slopes of s = 0.78 and s = 0.73 for reactions of MeO-2+ and Me-2+ , respectively. This shows that the sensitivity of bimolecular substitution at X-2+ to changes in nucleophile reactivity is smaller than for nucleophilic substitution at the methyl iodide. Evidence is presented that nucleophile addition to X-2+ proceeds through an "exploded" transition state.

Substituent Effects on the Formation and Nucleophile Selectivity of Ring-Substituted Phenonium Ions in Aqueous Solution.

The reaction of 2-(4-methyphenyl)ethyl tosylate (Me-1-OTs) in 50/50 (v/v) trifluoroethanol/water at 25 °C is first-order in the concentration of azide anion nucleophile. A carbon-13 NMR analysis of the products of the reactions of Me-1-[α-13C]OTs in 50/50 (v/v) trifluoroethanol/water at 25 °C shows the formation of Me-1-[ß-13C]OH, Me-1-[ß-13C]OCH2CF3 and Me-1-[ß-13C]N3 from the trapping of a symmetrical 4-methylphenonium ion reaction intermediate Me-2+. The formation of Me-1-[α-13C]N3 by concerted bimolecular displacement of azide ion at Me-1-[α-13C]OTs (kN = 3.8 × 10-6 M-1 s-1) and of Me-1-[α-13C]OH and Me-1-[α-13C]OCH2CF3 by concerted bimolecular displacement of solvent (ksolv = 1.8 × 10-8 s-1) is also observed. An analysis of the rate and product data provides a value of kaz/ks = 32 M-1 for partitioning of Me-2+ between addition of azide ion and solvent that is nearly 3-fold smaller than kaz/ks = 83 M-1 reported in an earlier study on the partitioning of MeO-2+ [J. Org. Chem.2011, 76, 9568]. This change is attributed to a decrease in nucleophile selectivity with increasing electrophile reactivity for the activation-limited addition of solvent and azide anion to X-2+. These data set a limit of 1/ks ≥ 10-7 s for the lifetime of Me-2+ in aqueous solution.

Formation and stability of the 4-methoxyphenonium ion in aqueous solution.

The reaction of 2-methoxyphenylethyl tosylate (MeO-1-Ts) is first-order in [N(3)(-)]. A carbon-13 NMR analysis of the products of the reactions of MeO-1-[α-(13)C]Ts shows the formation of MeO-1-[ß-(13)C]OH and MeO-1-[ß-(13)C]N(3) from the trapping of a symmetrical 4-methoxyphenonium ion reaction intermediate 2(+). An analysis of the rate and product data provides a value of k(az)/k(s) = 83 M(-1) for partitioning of 2(+) between addition of azide ion and solvent. These data set a limit for the lifetime of 2(+) in aqueous solution.

Interaction between Al3+ and acrylic acid and polyacrylic acid in acidic aqueous solution: a model experiment for the behavior of Al3+ in acidified soil solution.

From the viewpoint of the phytotoxicity and mobility of Al(3+) released from soil minerals due to soil acidification, the interaction between Al(3+) and acrylic acid (AA) and polyacrylic acid (PAA) as a model compound of fulvic acid was investigated. The interaction was examined at pH 3 so as to avoid the hydrolysis of Al(3+). The interaction between Al(3+) and AA was weak. However, the interaction between Al(3+) and PAA was strong and depended on the initial (COOH in PAA)/Al molar ratio (R(P)) of the solution. For the range of 1/R(P), the interaction between Al(3+) and PAA can be divided into three categories: (1) 1:1 Al-PAA-complex (an Al(3+) combines to a carboxyl group), (2) intermolecular Al-PAA-complex (an Al(3+) combines to more than 2 carboxyl groups of other Al-PAA-complexes) in addition to the 1:1 Al-PAA-complex and (3) precipitation of intermolecular complexes. In conclusion, R(P) is an important factor affecting the behavior of Al(3+) in acidic soil solution.

Formation of a silicato complex of zinc in aqueous solution and its accelerating effect on the formation of silica scales in cooling water systems.

This study elucidates the effect of zinc (Zn), which is an anticorrosive water additive, on the formation of silica scales from cooling water. In these experiments, the silica scales were analyzed by EPMA, and the results indicate that Zn is sorbed into the silica scales during formation. Measurements of the solubility of Zn(OH)(2) at various concentrations of silicic acid demonstrate that Zn is present as a silicato complex of Zn (SCZ) in cooling water. From adsorption experiments of the SCZ on silica and alumina, which are major components of the silica scales, it can be concluded that the SCZ accelerates the formation of silica scales from cooling water.

Dynamics for Reactions of Ion Pairs in Aqueous Solution: Reactivity of Tosylate Anion Ion Paired with the Highly Destabilized 1-(4-Methylphenyl)-2,2,2-Trifluoroethyl Carbocation.

The sum of the rate constants for solvolysis and scrambling of carbon bridging and nonbridging oxygen-18 at 4-MeC(6)H(4)CH(CF(3))OS((18)O(2))Tos in 50/50 (v/v) trifluoroethanol/water, (k(solv) + k(iso)) = 5.4 × 10(-6) s(-1), is 50% larger than k(solv) = 3.6 × 10(-6) for the simple solvolysis reaction of the sulfonate ester. This shows that the ion pair intermediate of solvolysis undergoes significant internal return to form reactant. These data give a value of k(-1) = 1.7 × 10(10) s(-1) for internal return of the carbocation-anion pair to the substrate. This rate constant is larger than the value of k(-1) = 7 × 10(9) s(-1) reported for internal return of an ion pair between the 1-(4-methylphenyl)ethyl carbocation and pentafluorobenzoate anion to the neutral ester (4-MeC(6)H(4)CH(CH(3))O(2)CC(6)F(5)) in the same solvent. The partitioning of ion pairs to the 1-(4-methylphenyl)ethyl carbocation and to the highly destabilized 1-(4-methylphenyl)2,2,2-trifluoroethyl carbocation is compared and contrasted.

When does an intermediate become a transition state? Degenerate isomerization without competing racemization during solvolysis of (S)-1-(3-nitrophenyl)ethyl tosylate.

(S)-1-(3-Nitrophenyl)ethyl tosylate [(S)-2-OTs] was prepared in >99% enantiomeric excess and the change in the chiral purity of this compound was monitored during solvolysis in 50:50 trifluoroethanol/water. The barely detectable formation of 0.5% (R)-2-OTs after two half times for the solvolysis reaction was used to calculate a rate constant of k(rac) approximately equal to 4 x 10-6 s-1. This is 80-fold smaller than kiso = 3.2 x 10-4 s-1 for the isomerization that exchanges oxygen-16 and oxygen-18 of 3-NO2C6H413CH(Me)OS(18O)2Tos during solvolysis and 10-fold smaller than the minimum value of k(rac) = 4.6 x 10-5 s-1 predicted if isomerization and racemization products form by partitioning of a common ion-pair intermediate of a stepwise reaction. It is concluded that the isomerization reaction proceeds mainly by a pathway that avoids formation of this putative intermediate. It is suggested that the solvolysis reaction of 2-OTs may proceed by a stepwise preassociation mechanism where solvent "reorganization" precedes substrate ionization to form an ion-pair intermediate.

[Prostate cancer detection by prostate biopsy among Japanese with prostate-specific antigen below 4.0 ng/ml].

The cases of prostate cancer diagnosed at our hospital after the introduction of transrectal ultrasound-guided prostate biopsy were analyzed to ascertain the cancer detection rate among individuals with a prostate-specific antigen (PSA) below 4.0 ng/ml and to assess the pathological characteristics of the prostatectomy specimens. During the period from January 1997 to December 2003, 1,167 individuals received prostate biopsies at our hospital. Before March 2003, the PSA cut-off level for biopsy was set at 4.0 ng/ml, but a biopsy was sometimes performed if a rectal examination revealed abnormalities or the patient desired a biopsy with a PSA below 4.0 ng/ml. After April 2003, all individuals with a PSA over 3.1 ng/ml were biopsied. The results of the prostate biopsy and the pathology data on radical prostatectomy specimens were compared between individuals with a PSA below 4.0 ng/ml and those with a PSA of 4.1-10 ng/ml. The prostate cancer detection rate among individuals with a PSA between 3.1 and 4.0 ng/ml was 19.4% (12/62) before March 2003 and 15.6% (7/45) after April 2003. The number of cancer-positive core was significantly lower among individuals with a PSA below 4.0 ng/ml. On prostatectomy specimens the percentage of surgical margin positive cases was significantly higher among individuals with a PSA below 4.0ng/ml (17 cases) than those with a PSA of 4.1-10 ng/ml (67 cases), although there was no significant difference between these two groups in terms of the pathological stage and Gleason score. Our results indicate that the prostate cancer detection rate is also high among Japanese men with a PSA below 4.0 ng/ml. The biopsy results and pathological features for prostate cancer with a PSA below 4.0 ng/ml did not differ markedly from prostate cancer with a PSA in the gray zone (4.1-10.0 ng/ml).

Reactions of ion-pair intermediates of solvolysis.

The detection during solvolysis of competing signature reactions such as the racemization of a chiral substrate, or the scrambling of oxygen isotopes at the leaving group serves as evidence for a stepwise mechanism that proceeds through a reversibly formed ion-pair intermediate. We have examined these signature reactions and determined the relative rates of competing solvolysis, isomerization, and racemization reactions of neutral ring-substituted 1-phenylethyl derivatives. These data were used to define the relative rate constants for partitioning of carbocation-anion pairs between dynamic processes such as reorganization of the ion pair within a solvent cage, and migration of the leaving group anion from the "top" to the "bottom" face of the planar carbocation. We present here a well-defined picture of the dynamics of these reactions in the mostly aqueous solvent of 50/50 (v/v) trifluoroethanol/water. A more complicated problem is the description of the changes in the reaction energy profiles for solvolysis, isomerization, and racemization reactions that occur as one destabilizes the carbocation intermediate of the stepwise reaction. We have examined the signature isomerization and racemization reactions of a ring-substituted 1-phenylethyl derivative that reacts by a "borderline" mechanism. We suggest that the signature isomerization reaction may in fact follow a concerted mechanism that bypasses the putative carbocation-anion pair intermediate.

Infection-induced urethral defect treated by urethral reconstruction with a radial forearm flap.

Abstract A 47-year-old man was admitted with the chief complaint of a urethral defect. An approximately 17-cm defect of the urethra seemed to have been occurred by the infection of implanted foreign bodies in the penile skin. Reconstruction of the urethra and the ventral skin was performed with a free radial forearm flap. A fistula formed at the proximal anastomosis after the operation, but was controlled conservatively. Urethral stricture at the proximal anastomosis subsequently developed. A urethral stent made of shape memory alloy was placed with the preservation of voiding function.

[A case of pyonephrosis caused by a protein calculus in a patient on hemodialysis].

We report a case of pyonephrosis caused by a protein calculus in a patient on hemodialysis. A 56-year-old man had been treated with dialysis for five years because of end-stage renal failure. The patient complained of right lumbar back pain and fever. Computed tomography and an ultrasonography revealed right hydronephrosis. Pyonephrosis was strongly suspected. A single-J catheter was indwelt, cloudy pus with a terrible smell was discharged. After reducing inflammation, a right nephrectomy was performed. The analysis of stone component revealed mostly a protein calculus, which was a black and turf-like substance in the calices. Patients undergoing dialysis often develop urinary calculi. Some calculi are composed of beta2-microglobulin-origin amyloid, which is very difficult to find with diagnostic imaging.

[Combination therapy with estramustine and docetaxel for hormone refractory prostate cancer].

Six patients with hormone refractory prostate cancer were orally administered 560 mg of Estramustine daily in 2 equally divided doses for four or five days. In addition 70 mg/m2 of Docetaxel was infused through intravenous drip from day 1, decreasing to 40-60 mg/m2 if any side effects such as bone marrow depression were observed. One cycle was three weeks in hospital and one month after discharge. Patients were treated until progression or the development of treatment-limiting toxicity. In five of the six patients (83.3%), serum prostate specific antigen (PSA) was decreased by more than 50%. Currently, this therapy is ongoing in four outpatients. A side effect of leucopenia (grade 2 or 3) was observed in all patients. Granulocyte-colony stimulating factor (G-CSF) formulation was given as treatment. One case was withdrawn due to loss of appetite after one cycle. This therapy is considered to be effective against hormone refractory prostate cancer. However, further examination is needed about dosage and dosing regimen of Estramustine and Docetaxel.

Scrambling of oxygen-18 during the "borderline" solvolysis of 1-(3-nitrophenyl)ethyl tosylate.

[reaction: see text] There is substantial isomerization (kiso=0.32 x 10(-3) s(-1)) of 3-NO2C6H4(13)CH(Me)OS(18O)2Tos during solvolysis (ksolv=1.04 x 10(-3) s(-1)) in 50/50 trifluoroethanol/water, even though the estimated lifetime of the putative 1-(3-nitrophenyl)ethyl carbocation intermediate of solvolysis (ca. 10(-13) s(-1)) is too short to allow rearrangement that exchanges the positions of 16O and 18O at the sulfonate leaving group. This suggests that isomerization proceeds by a mechanism that avoids formation of the carbocation-anion pair intermediate.

Early catheter removal and postoperative status of bladder outflow after retropubic radical prostatectomy.

Cystography was performed on 35 patients 6 to 7 days after retropubic radical prostatectomy (RRP), to determine the feasibility of early removal of the urinary catheter. The urethral catheter was removed the same day if no extravasation was evident on cystography. Uroflowmetry was also performed both immediately after early catheter removal and at follow-up 4 to 20 months later. The urethral catheter could be removed on postoperative day 6 or 7 from all but one patient. Three patients developed acute urinary retention after catheter removal, requiring reinsertion of a Foly catheter. During a mean follow-up of 8.3 months (range 4 to 20 months), 25 patients (71.4%) reported excellent continence (requiring no pad) and seven patients (20%) good continence (requiring a single pad). Immediately after early catheter removal, 12 patients (34%) showed obstruction on a maximum flow nomogram. The number of patients with obstruction decreased to eight during follow-up, three of whom suffered anastomotic stricture and one anterior urethral stricture, all of which required urethrotomy. Our results show that early catheter removal can be accomplished safely, although some patients may have difficulty with urination or develop acute urinary retention immediately after catheter removal, probably due to anastomotic edema. On the other hand, if the patients develop difficulty in urination some time after the operation, the possibility of anastomotic or urethral stricture should be considered. Therefore we recommend uroflowmetry within one year after RRP to identify anastomotic or urethral stricture.

Kinetic and thermodynamic barriers to carbon and oxygen alkylation of phenol and phenoxide ion by the 1-(4-methoxyphenyl)ethyl carbocation.

Rate constant ratios for addition of the three nucleophilic sites of phenol to the 1-(4-methoxyphenyl)ethyl carbocation (1+) in 50/50 (v/v) trifluoroethanol/water were determined from the relative yields of the three phenol adducts, and absolute rate constants were determined from product rate constant ratios for addition of phenol and azide ion to 1+ using k(az) = 5 x 10(9) M(-1) s(-1) for the diffusion-limited reaction of azide ion. A selectivity of 230:20:1 was determined for alkylation of phenol at oxygen, C-4 and C-2 to form 1-OPh and biphenyls 1-(4-C6H4OH) and 1-(2-C6H4OH), respectively, and of 2:2:1 for alkylation of the corresponding nucleophilic sites of phenoxide ion in diffusion-limited reactions. The Mayr nucleophilicity parameter for C-4 of phenol is N = 2.0. Encounter-limited addition of phenoxide ion to 1+ to form 1-OPh is faster than encounter-limited addition of oxygen anions that are either more or less basic than phenoxide ion. Only the products of solvolysis are observed from acid-catalyzed cleavage of 1-OPh in 50/50 (v/v) trifluoroethanol/water, but a 50% yield of biphenyls 1-(4-C6H4OH) and 1-(2-C6H4OH) are observed from spontaneous cleavage of 1-OPh, where the leaving group is phenoxide ion, because of the very low kinetic barriers to collapse of the ion pair intermediate 1+.PhO-. The 230-fold larger rate constant for O-compared to C-2-alkylation of phenol is due primarily to the larger thermodynamic driving force for oxygen addition. There are similar Marcus intrinsic barriers for these two reactions.

[Clinical study of chemoradiotherapy using low dose cisplatinum as X-ray intensifier in patients with urothelial carcinoma].

Chemoradiotherapy using cisplatinum (CDDP) as the X-ray intensifier was performed on patients with urothelial carcinoma. Ten lesions in 9 patients, 6 patients with postoperative relapse and 3 who received the therapy as a palliative treatment for progressive carcinoma, were evaluated. Four of the patients with postoperative relapse had undergone adjuvant chemotherapy. On the day of the treatment, the 9 patients were given continuous intravenous infusion of CDDP at the dose level of 5-12 mg/day prior to external irradiation at 50-66 Gy. The response to the therapy was categorized as complete response in 5 patients, partial response in 4, and no change in 1. The response rate was 90%, indicating achievement of a good local control. Pain relief and improvement of hydronephrosis were also observed in patients who underwent the therapy for treatment of progressive carcinoma. All adverse reactions were mild in intensity. These results suggest that the chemoradiotherapy is useful for both patient groups, those who have a postoperative relapse and those who undergo the therapy as a palliative treatment for progressive carcinoma.

3-(Trifluoromethyl)indenyl Cation: Ion Pair Return in the Formation of an Antiaromatic and Electron-Deficient Doubly Destabilized Carbocation.

The solvolysis of 3-(trifluoromethyl)-3-indenyl tosylate (15) occurs with extensive isomerization to 1-(trifluoromethyl)-3-indenyl tosylate (16), which reacts in a slower process to give the substitution product 17. Kinetic analysis of a model involving an intermediate allyl cation/tosylate ion pair 18 gave a partitioning ratio in CD(3)CO(2)D at 99.6 degrees C for 18 of 7.7 for return with allylic rearrangement compared with solvent capture. Studies of 15 with specific (18)O labeling show no scrambling in recovered 15 and partial scrambling in rearrangement to 16. The m value measuring the dependence of the reactivity of 15 on the solvent-ionizing parameter Y(OTs) is 0.78, which is significantly less than that of 1.23 for the analogous 9-(trifluoromethyl)-9-fluorenyl tosylate 7. Normal salt effects in CF(3)CO(2)H predominate for 15, and the special salt effect involves no more than 14% capture of solvent-separated ion pairs by 0.551 M KO(2)CCF(3). The substrate 15 has a net diminution in reactivity of more than 10(9) relative to the secondary indanyl tosylate 22, with factors of 10(6) and 10(3) attributable to antiaromaticity and to the electron-withdrawing CF(3) group, respectively. The solvolysis of 15 is proposed to occur by formation of an ion pair with significant nucleophilic solvation at the relatively unhindered allylic carbon, but internal return occurs in preference to solvent or salt capture. Solvolysis of the rearranged tosylate 16 occurs with a strong rate retardation by the gamma-CF(3) group, a large extent of internal return, and with a normal salt effect.