This contribution reviews all the synthetic work on tetrodotoxin that has appeared in the literature through June 2011.
A route to a racemic diene intermediate for the synthesis of tetrodotoxin is described. Key steps of the sequence leading to such a compound include the oxidative amidation of a phenol, a Cu(II)-catalyzed cyclocondensation of a nitroketone with an olefin (Machetti-DeSarlo reaction), and a nucleophilic fragmentation of the resulting isoxazoline. Several unusual reactions encountered in the course of this study are thoroughly discussed.
The molar Ken-constants of diphenyl and its 4-flUOrO-, -chloro-, -bromo-, -iodo-, -nitro-, and 2 : 2'and 3 : 3'-dinitro-derivatives are reported and discussed. They indicate a rough orthogonality of configuration for the last two molecules, and may be reconciled with flat configurations for the first six, among which conjugation is presumably causing a polarisability exaltation parallel to the 1 : 1'-bond.THE measurements now recorded were started in the hope that they would assist decisions on the configurations adopted by diphenyl and certain of its derivatives when present as solutes at room temperatures.The last thirty years' literature shows that configuration in this series is strongly affected by substitution. The diphenyl skeleton was originally expected by Le F h -e and Turner to possess a tendency to planarity owing to conjugation, opposed by the volumes and electrical effects of substituents; the hydrocarbon itself is now known by X-ray analysis and electron diffraction to be planar 2 in the crystal but non-planar in the vapour. Dipole moments in solution have indicated that 2 : 2'-dinitrodiphenyls have their rings rotated out of the cis-position so that the angles between them range from 70" to 90" and that these (azimuthal) angles are exceeded in the corresponding 3 : 3'isomers.the azimuthal angles are about 75", as in crystalline 6 2 : 2'-dichlorobenzidine (72") and 7 m-tolidine dihydrochloride (71") ; yet while 3 : 3'-dichlorobenzidine is non-planar (ca. 52") as a gas, it is stated as a solid to have the chlorine atoms disposed trans in a model which is flat or nearly so. No information by the above methods appears to exist concerning the configurations of 4-monosubst ituted diphenyls.Present Measurements.-Standard techniques being u~ed,~JO the dielectric constants, densities, electric double refractions, etc., have been observed for solutions of the solutes named in Tables 1 and 2. Symbols are defined in refs. 9 and 10.The dipole moments of the five monosubstituted diphenyls in Table 2 have the slight novelty of being determined in carbon tetrachloride instead of benzene.*J1 The values are qualitatively consistent with past studies of relationships between polarisation and medium (cf. ref. 9, Chap. 111).Discussion.-It is of interest to compare experimental molar Kerr constants with those calculable from known bond or group polarisabilities. Data by Le Fitvre and Purnachandra Rao l2 are relevant. For example, in computing , K for 2 : 2'-or 3 : 3'-dinitrodiphenyl, use can be made of the molecular semi-axes reported for nitrobenzene,12 vix., b, = 1.617, b, = 1.200, and b3 = 0.862 x c.c., where b, lies collinear with prMu1tant, b, collinear with the 2 : 6 direction, and b, perpendicular to the molecular plane.In gaseous 2 : 2'-dihalogeno-diphenyls
Measurements are recorded of the relaxation times of nitrobenzene, l-nitronaphthalene, 4-nitrodiphenyl, 9-nitroanthracene, benzophenone, fluorenone, pyridine, quinoline, isoquinoline, and acridine in a variety of solvents chosen from dioxan, p-xylene, carbon tetrachloride, benzene, toluene, cydohexane, H-heptane, and n-hexane. Equations are developed empirically, and tested against data from experiments, whereby T may be computed a @iwi from shape or polarisability ellipsoids of the solute molecules, and the viscosities, depolarisation factors, and dielectric constants of the solvents. DEBYE'S treatment of dielectric loss led to the well-known equation (1) for the relaxation time 7 of a molecule of radius r in a medium having a coefficient of inner friction ql* :As often used, with the macroscopic viscosity ql in place of the inaccessible ql*, and 9 deduced from the molecular volume, eqn. (1) yields values of 7 which may be 5-10 times those indicated by experiment. Two possible reasons for this are the non-equality of ql* and ql and the unreality of taking a sphere as a general model of all molecules. The former point has often been illustrated and attention was early drawn to the latter by P e~~i n ,~ who suggested essentially the substitution of 9 by the product of the three semi-axes of an ellipsoid. Perrin's idea has been elaborated by Fischer, Wirtz, and their collaborators! while improved approximations to ql* have been suggested by Hill ti and Hase; these proposals will be considered later. At the outset our objective was the modification of eqn. (1) to improve its applicability to the a 9rim-i computation of the relaxation times of solutes at infinite diIution. Some recent success with the use of shape factors in related fields encouraged the belief that they could be profitably introduced here. Accordingly the plan has been to determine 7 for a standard molecule (nitrobenzene), in eight solvents, to attempt to fit it with certain properties of the media, and then to test the validities of any expressions so achieved on a variety of other solutes, l-nitronaphthalene, 9-nitroanthracene, 44trodiphenyl; and pyridine, quinoline, acridine, and isoquinoline, chosen for their obvious stereochemical relationships with nitrobenzene and pyridine.Our results for relaxation times of nitrobenzene (10-l2 sec.) were as follows (that for carbon disulphide is due to Whiffen 8) : Dioxan 21 , p-xylene 14, carbon tetrachloride 14, benzene 11, toluene 11, carbon disulphide 8.6, cyclohexane 9-3,a-heptane 6.4, n-hexane 6.8. These values appear in reasonable agreement with others, as follows (references in parentheses) :
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