The organoselenium and organotellurium compounds have been described as promising pharmacological agents in view of their unique biological properties. Glutathione peroxidase mimic, antioxidant activity and thioredoxin reductase inhibition are some of the properties reviewed here. On the other hand, little is known about the molecular toxicological effects of organoselenium and organotellurium compounds. Most of our knowledge arose from research on inorganic selenium and tellurium. However, the ability to oxidize sulfhydryl groups from biological molecules can be involved both in their pharmacological properties and in their toxicological effects. In fact, exposition to high doses of organoselenium or to low doses of organotellurium causes the depletion of endogenous reduced glutathione in a variety of tissues. Thus, the design of compounds that cause low depletion of glutathione and react with specific targeted proteins, controlling specific metabolic pathways, will represent an important progress in understanding the field of organochalcogen compounds. Furthermore, the development of new organochalcogens with higher thiol-peroxidase activity that can use other non-toxic thiol reducing agents, such as N-acetylcysteine instead of glutathione, will permit the investigation of the co-administration of organochalcogens and thiols as a formulation for antioxidant therapy.

Organoselenium and Organotellurium Compounds: Toxicology and Pharmacology

Chemistry of biologically important synthetic organoselenium compounds.

Enzyme-like catalysis by molecularly imprinted polymers.

This review describes a multidimensional treatment of molecular recognition phenomena involving aromatic rings in chemical and biological systems. It summarizes new results reported since the appearance of an earlier review in 2003 in host-guest chemistry, biological affinity assays and biostructural analysis, data base mining in the Cambridge Structural Database (CSD) and the Protein Data Bank (PDB), and advanced computational studies. Topics addressed are arene-arene, perfluoroarene-arene, S⋅⋅⋅aromatic, cation-π, and anion-π interactions, as well as hydrogen bonding to π systems. The generated knowledge benefits, in particular, structure-based hit-to-lead development and lead optimization both in the pharmaceutical and in the crop protection industry. It equally facilitates the development of new advanced materials and supramolecular systems, and should inspire further utilization of interactions with aromatic rings to control the stereochemical outcome of synthetic transformations.

Aromatic rings in chemical and biological recognition: energetics and structures.

Tetrahedron report number 221

Phenyllithium forms a mixture of tetramer and dimer in ether. Complete conversion to dimeric solvates is achieved by the addition of THF, dioxolane, DME, or TMEDA in near stoichiometric amounts. The addition of 2,5-dimethyltetrahydrofuran favors dimer, but tetramer is still detectable at 14 equiv of cosolvent. PMDTA converts PhLi to monomer in ether. In THF, PhLi is a mixture of dimer and monomer. Addition of TMEDA forms a series of complexes, but the dimer/monomer ratio is essentially unaffected. PMDTA and HMPA form monomeric PhLi stoichiometrically. HMTTA and DMPU also result in monomer formation but several equiv are required. 12-Crown-4 shows no spectroscopically detectable complexation of PhLi in THF. All of the cosolvents tested increase the reactivity of PhLi in THF in a test metalation reaction: HMPA and 12-crown-4 show the largest effects, PMDTA is intermediate, and HMTTA and TMEDA result in the least activation. In two selectivity tests, HMPA and 12-crown-4 show a substantially lower selectivity than the other cosolvents. We postulate that a contribution from a highly reactive separated ion pair (SIP) intermediate is responsible for the lower selectivity.

Aggregation and Reactivity of Phenyllithium Solutions

Dibromination of [2.2]paracyclophane (I) led to predominantly pseudo-ortho2 (11) and pseudo-para2 (111) disubstituted compounds, and to lesser amounts of pseudo-meta (IV) and para (V) isomers. Oxidation of these dibromides gave terephthalic acids whose esters were identified by vpc, and whose structures allowed homoannular and transannular bromination to be differentiated. Tetrabromination of I gave compound VI with two p-bromines in each ring with a set of pseudo-ortho and a set of pseudo-para relationships between transannular bromines. This compound by lithiation and methylation of the organometallic gave the known tetramethyl[2.2]paracyclophane, VIII. Dibromination of dibromide I1 also gave VI. Compound VI1 was also isolated from the tetrabromination of I and the dibromination of 111; it contains two o-bromines in each ring with a set of pseudo-meta and a set of pseudo-para relationships between transannular bromines. Dehalogenation of VI1 with n-butyllithium in the presence of furan gave the bis(furan)benzyne adduct IX, which was converted to the known [2.2]paracyclonaphthane. Dibromide I11 was converted to dilithium derivative X. Methylation of X gave pseudo-p-dimethyl[2.2]paracyclophane2 (XI). Oxidation of X produced the pseudo-p-dihydroxy derivative, XII, and iodination, the pseudo-p-diiodo derivative, XIII. Dibromide I1 was also lithiated, and the dilithio derivative converted to pseudon-dihydroxy[2.2]paracyclophane2 (XVI). Attempts to oxidize diphenols XI1 and XVI to the corresponding bis quinones failed. Cuprous cyanide cyanation of pseudo-oor pseudo-p-dibromo compounds (I1 or 111) at 225 O gave, besides a mixture of I1 and 111, four compounds : pseudo-o-bromocyano[2.2]paracyclophane (XVIII), pseudop-bromocyano[2.2lparacyclophane (XIX), pseudo-o-dicyano[2.2]paracyclophane (XX), and pseudo-p-dicyano[2.21paracyclophane (XXI). Thermal isomerization by ring rotation accompanied substitution. The yield pattern showed no difference in activation or deactivation effects between the bromo and cyano groups toward the cyanation reaction. Chlorination of I was less discrete than bromination, and only pseudo-p-dichloro[2.2]paracyclophane (XXII) was isolated from a multitude of products. Dinitration of I gave four dinitro derivatives whose yield pattern revealed little evidence of a dominant transannular directive effect of a nitro group in one ring on the position of entry of a second into the transannular ring. The presence of the pseudo-gem isomer (XXIII), along with the pseudo-m(XXIV), pseudo-o(XXV), and pseudo-p(XXVI) dinitro[2.2]paracyclophanes, indicates the availability of the special mechanism for proton transfer in the pseudo-gem u complex for introduction of the second nitro group into the system. n paper XXXV of this series the patterns of transI annular directive influences of substituents in 4substituted [2.2]paracyclophanes on the positions of entry of electrophiles into the system were discussed. Bromination and acetylation reactions were found to substitute predominantly at those positions in the unsubstituted ring pseudo-gem2 to the most basic carbon or substituent in the originally substituted ring.3a Proton transfer from a u complex intermediate appeared to be the rate-limiting and product-determining step. In paper XXXVI, pseudo-gemand pseudo-metadisubstituted [2.2]paracyclophanes were found to equilibrate thermally at 200\", as were pseudo-ortho and pseudo-para isomers.3b Paper XXXVIII reports the determination of structure by nmr and mass spectral techniques3' of the large number of disubstituted [2.2]paracyclophanes reported in the three previous (1) The authors wish to thank the National Science Foundation for a grant used in support of this research. H. J. R. also wishes to acknowledge a Woodrow Wilson Fellowship (19641965) and a U. S. Rubber Co. tuition grant for 1967. (2) The colloquial nomenclature is self-evident : pseudo-gem denotes two transannularly adjacent positions on the benzene rings ; pseudoortho, pseudo-meta, and pseudo-para specify orrho, meta, and para relationships displaced from the usual homoannular into a transannular context. (3) (a) H. 3. Reich and D. J. Cram, J . Am. Chem. SOC., 91, 3505 (1969); (b) H. J. Reich and D. J. Cram, ibid., 91, 3517 (1969); (c) H. J. Reich and D. J. Cram, ibid., 91, 3534 (1969). papers. Correlations of physical properties with positions of substituents are also r ep~r t ed .~ ' This paper reports results of multiple halogenation and nitration reactions of [2.2]paracyclophane, and of conversions of halo-substituted [2.2]paracyclophanes into other substituted compounds. This ring system is highly rigid,4 and can act as a scaffold for placing functional groups in set geometric relationships to one another for systematic studies of transannular and multiple functional group effects on physical and chemical properties. This study is concerned with development of synthetic methods whose ultimate objective is to bring to hand any desired multiply substituted [2.2]paracyclophane. Direct introduction of two or more bromine5 or chlorine and of two nitro groups6 has been reported, but without fully distinguishing isomeric structures. Metalation and cyanation of mono and dihalo derivatives of [2.2]paracyclophane have been previously r e p ~ r t e d . ~ ' ~ (4) P. K. Gantzel and K. N. Trueblood, Acta Cryst., 18, 958 (1965). (5) (a) W. F. Gorham, Candian Patent 638,335 (1962); (b) Y. L. Yeh, U. S. Patent 3,155,172 (1962); (c) Y. L. Yeh, U. S. Patent 3,349,124 (1967); (d) Y. L. Yeh, Canadian Patent 705,457 (1965); (e) Y. L. Yeh, Canadian Patent 772,189 (1967); (f) Y. L. Yeh, U. S Patent 3,155,712 (1964); (g) W. F. Gorham, U. S. Patent 3,117,168 (1964); (h) Y. L. Yeh and W. F. Gorham, J . Org. Chem., in press; (i) D. J. Cram and A. C. Day, ibid., 31,1227 (1966). (6) D. J. Cram, R. H. Bauer, N. L. Allinger, R. A. Reeves, w. J. Wechter, and E. Heilbronner, J . Am. Chem. SOC., 81,5977 (1959). Reich, Cram Electrophilic Substitutions in [2.2lParacyclophane~

Macro rings. XXXVII. Multiple electrophilic substitution reactions of [2.2]paracyclophanes and interconversions of polysubstituted derivatives

This Perspective describes a series of research projects that led the author from an interest in lithium reagents as synthetically valuable building blocks to studies aimed at understanding the science behind the empirical art developed by synthetic chemists trying to impose their will on these reactive species Understanding lithium reagent behavior is not an easy task; since many are mixtures of aggregates, various solvates are present, and frequently new mixed aggregates are formed during their reactions with electrophiles All of these species are typically in fast exchange at temperatures above −78 °C Described are multinuclear NMR experiments at very low temperatures aimed at defining solution structures and dynamics and some kinetic studies, both using classic techniques as well as the rapid inject NMR (RINMR) technique, which can in favorable cases operate on multispecies solutions without the masking effect of the Curtin–Hammett principle

What’s Going on with These Lithium Reagents?

Low-temperature rapid injection NMR (RINMR) experiments were performed on two lithium reagents, n-butyllithium and 2-methoxy-6-(methoxymethyl)phenyllithium (5), with the goal of measuring the relative reactivity of the different aggregates (dimer, mixed dimer, and tetramer for n-BuLi, monomer and tetramer for 5) toward typical electrophiles. The reaction of the n-BuLi dimer with (trimethylsilyl)acetylene first forms the mixed dimer n-BuLi·Me3SiC⋮CLi, which is about 1/60 as reactive as the n-BuLi homodimer. The tetramer does not react. In the deprotonation of (phenylthio)acetylene, the n-BuLi dimer was found to be 3.5 × 108 as reactive as the tetramer, and in the addition to p-diethylaminobenzaldehyde, the relative reactivity was at least 2 × 104. In the deprotonation of (p-tolylsulfonyl)acetylene, the monomer of 5 was at least 1014 times as reactive as the tetramer. These measurements show that the difference in reactivity between the lower and higher aggregates of organolithium reagents can be many order...

Hans J. Reich

Papers

Aggregation and Reactivity of Phenyllithium Solutions

Macro rings. XXXVII. Multiple electrophilic substitution reactions of [2.2]paracyclophanes and interconversions of polysubstituted derivatives

What’s Going on with These Lithium Reagents?

Reactivity of individual organolithium aggregates: a RINMR study of n-butyllithium and 2-methoxy-6-(methoxymethyl)phenyllithium.

Macro rings. XXXVI. Ring expansion, racemization, and isomer interconversions in the [2.2]paracyclophane system through a diradical intermediate