Assay of the chiral organophosphate, soman, in biological samples

The anticholinesterase, soman, (CH3)3CC(H)CH3O(CH3)P(O)F, consists of four stereoisomers assigned as C(+/-)P(+/-)-soman in which C stands for chirality in the pinacolyl moiety and P for chirality at phosphorus. The four stereoisomers are separated by gas chromatography on an optically active Chirasil-Val column, synthesized and coated in house, or on a Chirasil-Val column identical with the commercially available column when combined with a Carbowax 20M column. This method in combination with an assay based on acetylcholinesterase inhibition shows that the two isomers which do not have anticholinesterase activity, i.e. C(+/-)P(+/-)-soman, are rapidly degraded in rat blood due to hydrolysis by phosphorylphosphatases. Epimeric soman isomers, e.g. C(+/-)P(-)-soman, can be separately assayed on a Carbowax or a CPSil 8 column, using 2H-labeled soman isomers as internal standards. 2H-labeled soman stereoisomers serve as internal standards in GC-assay of all four stereoisomers on Chirasil-Val. For work-up of the four stereoisomers from rat blood the sample is first stabilized by acidification to pH 4.2 at 0 degree C to suppress hydrolysis by phosphorylphosphatases, addition of aluminum ions for complexation of fluoride ions to prevent regeneration of C(+/-)P(-)-soman by free fluoride ions from soman-inhibited carboxylesterase, and addition of (CH3)3CCH2O(CH3)P(O)F to occupy covalent binding sites for C(+/-)P(-)-soman, before extraction with a Sep-Pak C18 cartridge and elution with ethyl acetate. Using a splitless or on-column injection technique and alkali flame ionization detection, the minimum detectable concentration is 30 pg/3-ml blood sample.     

The pK(a) of the internucleotidic 2'-hydroxyl group in diribonucleoside (3'-->5') monophosphates

Ionization of the internucleotidic 2'-hydroxyl group in RNA facilitates transesterification reactions in Group I and II introns (splicing), hammerhead and hairpin ribozymes, self-cleavage in lariat-RNA, and leadzymes and tRNA processing by RNase P RNA, as well as in some RNA cleavage reactions promoted by ribonucleases. Earlier, the pK(a) of 2'-OH in mono- and diribonucleoside (3'-->5') monophosphates had been measured under various nonuniform conditions, which make their comparison difficult. This work overcomes this limitation by measuring the pK(a) values for internucleotidic 2'-OH of eight different diribonucleoside (3'-->5') monophosphates under a set of uniform noninvasive conditions by 1H NMR. Thus the pK(a) is 12.31 (+/-0.02) for ApG and 12.41 (+/-0.04) for ApA, 12.73 (+/-0.04) for GpG and 12.71 (+/-0.08) for GpA, 12.77 (+/-0.03) for CpG and 12.88 (+/-0.02) for CpA, and 12.76 (+/-0.03) for UpG and 12.70 (+/-0.03) for UpA. By comparing the pK(a)s of the respective 2'-OH of monomeric nucleoside 3'-ethyl phosphates with that of internucleotidic 2'-OH in corresponding diribonucleoside (3'-->5') monophosphates, it has been confirmed that the aglycons have no significant effect on the pK(a) values of their 2'-OH under our measurement condition, except for the internucleotidic 2'-OH of 9-adeninyl nucleotide at the 5'-end (ApA and ApG), which is more acidic by 0.3-0.4 pK(a) units.     

(S)-(+)-2-octanol as a chiral oil core for the microemulsion electrokinetic chromatographic separation of chiral basic drugs.

The enantiomeric separation of basic drugs was successfully demonstrated by using a novel chiral microemulsion electrokinetic chromatography (MEEKC). An interesting finding was that the chiral oil core ((S)-(+)-2-octanol) within the microemulsion droplets appeared to play an important role in the chiral separation mechanism. In addition, the enantioselectivity of the analyte-selector complex could be influenced by methanol, through an interaction with the complex. The chiral resolution (R(s)) and partition coefficient were strongly influenced by the concentration of methanol, pH, the concentration of chiral oil and the concentration of a cosurfactant. Under the optimized microemulsion conditions, the baseline separation of (+/-)-ephedrine (R(s) = 2.7), and the partial separations of (+/-)-norephedrine (R(s) = 1.3), (+/-)-synephrine (R(s) = 1.4) and (+/-)-propranolol (R(s) = 1.3), could be achieved.     

Synthesis of some members of the hydroxylated phenanthridone subclass of the Amaryllidaceae alkaloid family

The total synthesis of several members of the hydroxylated phenanthridone subclass of the Amaryllidaceae alkaloid family has been carried out. (+/-)-Lycoricidine and (+/-)-7-deoxypancratistatin were assembled through a one-pot Stille/intramolecular Diels-Alder cycloaddition cascade to construct the core skeleton. The initially formed [4+2]-cycloadduct undergoes nitrogen-assisted ring opening followed by a deprotonation/reprotonation of the resulting zwitterion to give a rearranged hexahydroindolinone on further heating at 160 degrees C. The stereochemical outcome of the IMDAF cycloaddition has the side arm of the tethered vinyl group oriented exo with respect to the oxygen bridge. The resulting cycloadduct was used for the stereocontrolled installation of the remaining functionality present in the C-ring of the target molecules. Key features of the synthetic strategy include (1) a lithium hydroxide induced tandem hydrolysis/decarboxylation/elimination sequence to introduce the required pi-bond in the C-ring of (+/-)-lycoricidine, and (2) conversion of the initially formed Diels-Alder adduct into an aldehyde intermediate which then undergoes a stereospecific decarbonylation reaction mediated by Wilkinson's catalyst to set the trans-B-C ring junction of (+/-)-7-deoxypancratistatin.     

Proton exchange kinetics from the bound waters on the oxo-centered rhodium(III) trimer [Rh3(mu3-O)(mu-O2CCH3)6(OH2)3]+: a variable pH and temperature 1H NMR study

Proton exchange from the bound to the bulk waters on the oxo-centered rhodium(III) trimer, [Rh(3)(micro(3)-O)(micro-O(2)CCH(3))(6)(OH(2))(3)](+)(abbreviated as Rh(3)(+)), was investigated over the temperature range of 219.1-313.9 K using a (1)H NMR line-broadening technique. By solving the modified Bloch equations for a two-site chemical exchange, lifetimes (tau) for proton transfer at pH = 2.7, 3.6, and 7.0 ([Rh(3)(+)]= 26 mM, T= 298 K) were determined to be 0.3 (+/-.08) ms, 2 (+/-0.3) ms, and 0.2 (+/-0.2) ms, respectively. From the temperature dependence of the rate, the activation parameters were determined to be DeltaH(++)= 16.2 (+/-0.5) kJ mol(-1) and DeltaS(++)=- 123 (+/-2) J mol(-1) K(-1), DeltaH(++)= 14.9 (+/-0.5) kJ mol(-1) and DeltaS(++)=- 141 (+/-2) J mol(-1) K(-1), and DeltaH(++)= 45 (+/-2) kJ mol(-1) and DeltaS(++)=- 22 (+/-5) J mol(-1) K(-1) for pH = 2.7, 3.6 and 7.0, respectively. All results are reported for a mixed solvent system [acetone : 250 mM NaClO(4)(aq)(3:1)], which was necessary to depress the freezing point of the solution so that the (1)H NMR signal due to bound water could be observed. The pK(a) of Rh(3)(+) was measured to be 8.9 (+/-0.2) in the mixed solvent, which is near the pK(a) for an aqueous solution (8.3 (+/-0.2)). Surprisingly, the lifetimes for protons on Rh(3)(+) are close to those observed for the Rh(OH(2))(6)(3+) ion, in spite of the considerable difference in structure, Br?nsted acidity of the bound waters and average charge on the metal ion.     

Synthesis of aromatic bisabolene natural products via palladium-catalyzed cross-couplings of organozinc reagents

Aromatic bisabolene derivatives were prepared by two methods involving cross-coupling of organozinc reagents. The first synthesis of (+/-)-glandulone A (10), as well as syntheses of (+/-)-curcuhydroquinone (8) and (+/-)-curcuquinone (9), were accomplished via coupling of a secondary alkyl zinc reagent (1,5-dimethyl-4-hexenylzinc halide, 18) to protected bromohydroquinones using Pd(dppf)Cl(2) as catalyst. Coupling of arylzinc halides with alkenyl triflate 16 using Pd(PPh(3))(4) catalyst provided a number of bisabolene derivatives and led to syntheses of dehydro-alpha-curcumene (2), (+/-)-curcuphenol (3), and (+/-)-elvirol (13). A high-yield synthesis of the (+/-)-heliannuol D precursor 29 is also reported using this method.     

The first example of a nitrile hydratase model complex that reversibly binds nitriles

Nitrile hydratase (NHase) is an iron-containing metalloenzyme that converts nitriles to amides. The mechanism by which this biochemical reaction occurs is unknown. One mechanism that has been proposed involves nucleophilic attack of an Fe-bound nitrile by water (or hydroxide). Reported herein is a five-coordinate model compound ([Fe(III)(S(2)(Me2)N(3)(Et,Pr))](+)) containing Fe(III) in an environment resembling that of NHase, which reversibly binds a variety of nitriles, alcohols, amines, and thiocyanate. XAS shows that five-coordinate [Fe(III)(S(2)(Me2)N(3)(Et,Pr))](+) reacts with both methanol and acetonitrile to afford a six-coordinate solvent-bound complex. Competitive binding studies demonstrate that MeCN preferentially binds over ROH, suggesting that nitriles would be capable of displacing the H(2)O coordinated to the iron site of NHase. Thermodynamic parameters were determined for acetonitrile (DeltaH = -6.2(+/-0.2) kcal/mol, DeltaS = -29.4(+/-0.8) eu), benzonitrile (-4.2(+/-0.6) kcal/mol, DeltaS = -18(+/-3) eu), and pyridine (DeltaH = -8(+/-1) kcal/mol, DeltaS = -41(+/-6) eu) binding to [Fe(III)(S(2)(Me2)N(3)(Et,Pr))](+) using variable-temperature electronic absorption spectroscopy. Ligand exchange kinetics were examined for acetonitrile, iso-propylnitrile, benzonitrile, and 4-tert-butylpyridine using (13)C NMR line-broadening analysis, at a variety of temperatures. Activation parameters for ligand exchange were determined to be DeltaH(+ +) = 7.1(+/-0.8) kcal/mol, DeltaS(+ +) = -10(+/-1) eu (acetonitrile), DeltaH(+ +) = 5.4(+/-0.6) kcal/mol, DeltaS(+ +) = -17(+/-2) eu (iso-propionitrile), DeltaH(+ +) = 4.9(+/-0.8) kcal/mol, DeltaS(+ +) = -20(+/-3) eu (benzonitrile), and DeltaH(+ +) = 4.7(+/-1.4) kcal/mol DeltaS(+ +) = -18(+/-2) eu (4-tert-butylpyridine). The thermodynamic parameters for pyridine binding to a related complex, [Fe(III)(S(2)(Me2)N(3)(Pr,Pr))](+) (DeltaH = -5.9(+/-0.8) kcal/mol, DeltaS = -24(+/-3) eu), are also reported, as well as kinetic parameters for 4-tert-butylpyridine exchange (DeltaH(+ +) = 3.1(+/-0.8) kcal/mol, DeltaS(+ +) = -25(+/-3) eu). These data show for the first time that, when it is contained in a ligand environment similar to that of NHase, Fe(III) is capable of forming a stable complex with nitriles. Also, the rates of ligand exchange demonstrate that low-spin Fe(III) in this ligand environment is more labile than expected. Furthermore, comparison of [Fe(III)(S(2)(Me2)N(3)(Et,Pr))](+) and [Fe(III)(S(2)(Me2)N(3)(Pr,Pr))](+) demonstrates how minor distortions induced by ligand constraints can dramatically alter the reactivity of a metal complex.     

2,6-二-O-戊基-β-环糊精涂渍Symmetry C8柱拆分扁桃酸及其类似物对映体

利用合成的2,6-二-O-戊基-β-环糊精涂渍Symmetry C8色谱柱,研究了扁桃酸及其类似物等6 种外消旋对映体的反相高效液相色谱拆分。优化了色谱分离条件,探讨了扁桃酸的手性拆分机理。结果表明,采用优化后的甲醇-水或甲醇-0.5%三乙胺-乙酸缓冲液流动相等色谱条件,扁桃酸、扁桃酸甲酯、苯基甘氨酸、苯基琥珀酸和安息香等5种外消旋对映体达到或接近基线分离,其中前4种对映体均为(S)-构型先出峰。该法可用于实际样品的对映体纯度测定。     

A formal total synthesis of the sesterterpenoid (+/-)-dysidiolide and approaches to the syntheses of (+/-)-6-epi-, (+/-)-15-epi-, and (+/-)-6,15-bisepidysidiolide

A formal total synthesis of the sesterterpenoid (+/-)-dysidiolide (1), a structurally novel sponge metabolite that inhibits the cdc25A protein phosphatase, and approaches to the syntheses of (+/-)-15-epi- (34), (+/-)-6-epi- (36), and (+/-)-6, 15-bisepidysidiolide (39) are described.     

Total synthesis of nor-1,6-germacradien-5-ols

The first total synthesis of (+/-)-nor-1,6-germacradien-5-ols is described. The synthetic route involves the RCM methodology for the ring formation and a selective 1,2 addition of MeLi to cyclodecenone. By altering the order of the last synthetic steps, TBSO-protected (+/-)-(1Z,6E)-nor-1,6-germacradien-5-ols (+/-)-(5S*,8R*)-16 and -(+/-)-(5S*,8S*)-16 were obtained. The synthetic strategy via cyclodecenone offers the possibility of preparing different analogues of the title compounds through addition of other nucleophiles. Moreover, nor-germacrene D could be accessed from the target molecule by methylenation of its carbonyl moiety. (+/-)-nor-1,6-Germacradien-5-ol [(+/-)-(1E,5S*,6E,8S*)-2] was synthesized in eight steps from isovaleric acid. The 10-membered ring was formed by RCM, and the tertiary alcohol moiety was introduced in the last step via a highly diastereoselective addition of MeLi to (+/-)-(1E,6E)-1,6-cyclodecen-5-one (+/-)-E,E-5. Addition of MeLi to cyclodecenone (+/-)-Z,E-5 also occurred with complete selectivity to provide (+/-)-(1Z,5S*,6E,8S*)-2. A slightly different synthetic pathway was also explored, in which the order of the final synthetic steps was switched: the enone formation and the addition of MeLi were conducted prior to the cyclization. When the hydroxy group was protected as a TBS ether, the newly formed olefin had exclusively Z configuration. Thus, TBSO-protected (+/-)-(1Z,6E)-nor-1,6-germacradien-5-ols (+/-)-16 were obtained as a 1:1 (5S*,8S*)/(5R*,8S*) mixture. The NMR spectra of these two diastereomers confirmed the relative stereochemistry of natural (-)-1,6-germacradien-5-ol (1) at C5 and C8.     

Disinfection of drinking water contaminated with Cryptosporidium parvum oocysts under natural sunlight and using the photocatalyst TiO2

The results of a batch-process solar disinfection (SODIS) and solar photocatalytic disinfection (SPCDIS) on drinking water contaminated with Cryptosporidium are reported. Cryptosporidium parvum oocyst suspensions were exposed to natural sunlight in Southern Spain and the oocyst viability was evaluated using two vital dyes [4',6-diamidino-2-phenylindole (DAPI) and propidium iodide (PI)]. SODIS exposures (strong sunlight) of 8 and 12h reduced oocyst viability from 98% (+/-1.3%) to 11.7% (+/-0.9%) and 0.3% (+/-0.33%), respectively. SODIS reactors fitted with flexible plastic inserts coated with TiO2 powder (SPCDIS) were found to be more effective than those which were not. After 8 and 16 h of overcast and cloudy solar irradiance conditions, SPCDIS reduced oocyst viability from 98.3% (+/-0.3%) to 37.7% (+/-2.6%) and 11.7% (+/-0.7%), respectively, versus to that achieved using SODIS of 81.3% (+/-1.6%) and 36.0% (+/-1.0%), respectively. These results confirm that solar disinfection of drinking water can be an effective household intervention against Cryptosporidium contamination.     

Using the Pummerer cyclization-deprotonation-cycloaddition cascade of imidosulfoxides for alkaloid synthesis

The Pummerer reaction of imidosulfoxides bearing tethered alkenyl groups has been employed for the synthesis of several alkaloids. The required imidosulfoxides necessary for the cascade sequence were easily obtained by heating the appropriate amide with (ethylsulfeny)acetyl chloride followed by sodium periodate oxidation. The initially formed thionium ion, obtained by treating the imidosulfoxide with acetic anhydride and p-toluenesulfonic acid, reacts with the neighboring imido group, and the resulting oxonium ion undergoes subsequent deprotonation to produce an isomünchnone dipole. This mesoionic betaine intermediate undergoes ready intramolecular dipolar cycloaddition across the neighboring pi-bond. Exposure of the resulting cycloadducts to additional acetic anhydride leads to ring opening and formation of a 5-acetoxy-substituted 2(1H)-pyridone. This six-ring heterocyclic system constitutes a valuable building block for the synthesis of a variety of pyridine, quinolizidine, and clavine alkaloids. The cyclization-deprotonation-cycloaddition cascade has been successfully applied to the synthesis of the naturally occurring alkaloids onychnine, dielsiquinone, (+/-)-lupinine, (+/-)-anagyrine, (+/-)-pumiliotoxin C, and (+/-)-costaclavine.     

Electrocyclic ring-opening/pi-allyl cation cyclization reaction sequences involving gem-dihalocyclopropanes as substrates: application to syntheses of (+/-)-, (+)-, and (-)-gamma-lycorane

The readily prepared gem-dibromocyclopropanes (+/-)-13 and (+/-)-19 each engage in a silver(I)-promoted electrocyclic ring-opening/pi-allyl cation cyclization sequence to deliver the hexahydroindole (+/-)-20, which participates in a Suzuki cross-coupling reaction with arylboronic acid 3 to give the tetracyclic compound (+/-)-21. Catalytic hydrogenation of this last compound proceeds in a completely stereoselective manner to give the saturated analogue (+/-)-24, which undergoes Bischler-Napieralski cyclization on reaction with phosphorus oxychloride. The resulting lactam (+/-)-25 is then reduced with lithium aluminum hydride to give (+/-)-gamma-lycorane [(+/-)-1]. By using (-)-menthyl-derived carbamates 27 and 28, this chemistry has been extended to the synthesis of the (+)- and (-)-modifications of the title compound.     

Energetics and role of the hydrophobic interaction during photoreaction of the BLUF domain of AppA

A recently developed method for time-resolved thermodynamic measurements was used to study the photochemical reaction(s) of the BLUF domain of AppA (AppA-BLUF), which has a dimeric form in the ground state, in terms of the energetics and heat capacity changes (DeltaC(p)) in different time domains. The enthalpy change (DeltaH) of the first intermediate that forms within 1 ns after photoexcitation was 38 (+/-8) kJ mol(-1) at 298 K. The heat capacity change (DeltaC(p)) upon formation of this intermediate was positive [1.4 (+/-0.3) kJ mol(-1) K(-1)]. This positive DeltaC(p) suggests that the hydrophobic surface area of AppA-BLUF exposed to the bulk solvent increased. After this initial transition, a dimerization reaction with another ground-state dimer (i.e., tetramer formation) takes place. Upon this reaction, the energy was stabilized to 26 (+/-6) kJ mol(-1) at 298 K. Interestingly, the dimer formation was accompanied by a larger but negative DeltaC(p) [-6.0 (+/-1) kJ mol(-1) K(-1)]. This negative DeltaC(p) might indicate buried hydrophobic residues at the interface of the dimer and/or the existence of trapped water at the interface. We suggest that hydrophobic interactions are the main driving force for the formation of the dimer upon photoactivation of AppA-BLUF.     

Chemoenzymatic preparation of optically active trans-cyclohexane-1,2-diamine derivatives: an efficient synthesis of the analgesic U-(-)-50,488

Stereoespecific syntheses of (+/-)-trans-N,N-cyclohexane-1,2-diamines ((+/-)-4 a-g) were carried out from the corresponding (+/-)-trans-N,N-dialkylaminocyclohexanols by successive treatment with mesyl chloride and aqueous ammonia. The stereochemical outcome indicates the formation of a meso-aziridinium ion intermediate. Kinetic resolutions of diamines (+/-)-4 were efficiently accomplished in aminolysis reactions catalyzed by lipase B from Candida antarctica with ethyl acetate as the solvent and acyl donor. Acetamides and the remaining diamines, isolated as the benzyloxycarbonyl derivatives, were obtained with very high ee values (92-99%). One of the carbamates was used as a precursor of the analgesic U-(-)-50,488.     

A general synthetic entry to the pentacyclic strychnos alkaloid family, using a [4 + 2]-cycloaddition/rearrangement cascade sequence

The total synthesis of (+/-)-strychnopivotine, (+/-)-tubifolidine, (+/-)-strychnine, and (+/-)-valparicine is reported. The central step in the synthesis consists of an intramolecular [4 + 2]-cycloaddition/rearrangement cascade of an indolyl-substituted amidofuran that delivers an aza-tetracyclic substructure containing the ABCE-rings of the Strychnos alkaloid family. A large substituent group on the amide nitrogen atom causes the reactive s- trans conformation of the amidofuran to be more highly populated, thereby facilitating the Diels-Alder cycloaddition. The reaction also requires the presence of an electron-withdrawing substituent on the indole nitrogen for the cycloaddition to proceed. The cycloaddition/rearrangement cascade was remarkably efficient given that two heteroaromatic systems are compromised in the reaction. Closure to the remaining D-ring of the Strychnos skeleton was carried out from the aza-tetracyclic intermediate by an intramolecular palladium-catalyzed enolate-driven cross-coupling between the N-tethered vinyl iodide and the keto functionality. The cycloaddition/rearrangement approach was successfully applied to (+/-)-strychnopivotine (2), the only Strychnos alkaloid bearing a 2-acylindoline moiety in its pentacyclic framework. A variation of this tactic was then utilized for a synthesis of the heptacyclic framework of (+/-)-strychnine. The total synthesis of (+/-)-strychnine required only 13 steps from furanyl indole 18 and proceeded in an overall yield of 4.4%.     

Enantiomer separation by counter-current chromatography. Optimisation and drawbacks in the use of L-proline derivatives as chiral selectors

Several L-proline and (4R)-hydroxy-L-proline derivatives were evaluated as chiral selectors (CSs) in the separation of enantiomers by counter-current chromatography (CCC). A variety of biphasic solvent systems, all of organic/aqueous nature, were tested in order to determine the appropriate distribution for CSs and racemates (N-(3,5-dinitrobenzoyl)-(+/-)-leucine and (+/-)-ketoprofen). Successful separations of DNB-(+/-)-leucine in analogous experimental conditions allow the comparative study of the enantioselectivity displayed by the considered CSs. The low solubility of certain CSs limits their applicability for preparative purposes even for improved enantioselectivity. The effect that the nature and pH of the buffer solutions used as a component of the solvent system have on the separation was also studied.     

Application of furanyl carbamate cycloadditions toward the synthesis of hexahydroindolinone alkaloids

A convenient synthesis of various substituted hexahydroindolinones has been achieved by an intramolecular Diels--Alder cycloaddition reaction (IMDAF) of furanyl carbamates bearing tethered alkenyl groups. The initially formed [4 + 2]-cycloadduct undergoes nitrogen-assisted ring opening followed by deprotonation of the resulting zwitterion to give the rearranged ketone. The stereochemical outcome of the IMDAF cycloaddition has the sidearm of the tethered alkenyl group oriented syn with respect to the oxygen bridge. A synthetic route to (+/-)-mesembrane and (+/-)-crinane was accomplished using this methodology. It was possible to carry out a stereoselective reduction of the initially formed hexahydroindolinone ring to produce the cis-3a-aryl-hydroindole skeleton. A related [4 + 2]-cycloaddition/rearrangement sequence was also used for a formal synthesis of the Chinese ornamental orchid (+/-)-dendrobine. The tricyclic alkaloid core was formed stereoselectivity from the thermolysis of N-[(2-methyl-2-cyclopentenyl)methyl]-N-(4-isopropyl-furan-2-yl)carbamic acid tert-butyl ester. Kende's advanced intermediate 33 was prepared in seven additional steps by standard transformations, thereby completing a formal synthesis of (+/-)-dendrobine.     

The first structural characterization and determination of the isomerization activation parameters of a chiral phosphatitanocene

The activation parameters (delta G++298 = 11.5 (+/- 1.0) kcal mol-1, delta H++ = 16.3 (+/- 3.0) kcal mol-1, delta S++ = 16 (+/- 11) cal mol-1 K-1) have been determined for the rac to meso isomerization of a phosphametallocene, bis(3,4-dimethyl-2-phenylphospholyl)titanium dichloride, 2, which has been structurally characterized.