CAL Y. MEYERS joined the faculty of Southern Illinois University at Carbondale in 1964. He received his B.A. degree from Cornell University in 1948 and Ph.D. from the University of Illinois in 1951, after which he carried out postdoctoral research on the chemistry of adrenocortical steroids at Princeton University for two years, sponsored largely by Merck, Inc. During 1953-1960 he carried out research at Union Carbide Corp. and initiated studies on new heat-resistant polyarylsulfone resins. He was Visiting Professor of organic chemistry at the University of Bologna, Italy, during 1960-1963 and Visiting Scholar in organic chemistry at UCLA in 1963-1964, prior to coming to Southern Illinois University at Carbondale.
RESEARCH INTERESTS
His research groups have investigated many aspects of reaction mechanisms, single-electron-transfer (SET) reactions, carbanion reactivity, organosulfur chemistry, doisynolic-acid estrogens, phase-transfer deprotonations-D/H exchange, and stereo-chemistry of 9-substituted fluorenes and urazole-related compounds. A continuing study has focused on the rela-tive proton-acceptor, nucleophilic, and SET reactivity of carbanions and related species. SET pathways were found to be responsible for the rapid halogenation of carbanions with perhaloalkanes [radical/anion radical pair (RARP) mechanism]. Chlorinations effected with CCl4/KOH may be followed by other reactions in situ, constituting important synthetic routes. Cations can react with anions via a direct nucleophilc attack or via an SET pathway, sometimes leading to different products. Some illustrative examples are: -Dialkyl sulfones are transformed into cis-1,2-dialkylethenesulfonates, excellent surfac-tants now incorporated into a patented method to remove pyritic sulfur from coal. -Trityl chloride reacts with alkoxide anions via a direct nucleophilic attack to yield only the trityl alkyl ether. With thioalkoxides, however, thioalkylation occurs on an aromatic ring as well as on the central carbon, the former via an electron-transfer process. -Estrone and estradiol are converted into doisynolic acids, which are similar to estra-diol in in vivo estrogenicity but show little activity against 3H-estradiol in competitive estrogen-receptor binding-affinity studies, suggesting the presence of estrogen receptors other than the "classic" estradiol receptor ("ER"). This concept is now being examined under a joint NIH grant with Stuart Adler, M.D.-Ph.D., at Washington University School of Medicine-Barnes-Jewish Hospital.
SET routes ("soft") versus ionic routes ("hard") were evaluated in comparing the re-activity of ambident nucleophilic sites--e.g. S- versus O-alkylation of sulfoxides and su-finate anions with R-I and R-OTs ("soft" and "hard" electrophiles, respectively).
The failure of the deprotonation of CH2Cl2 by HO-/H2O to any detectable extent was demonstrated and shown to be overcome by phase-transfer catalysis, which became the key to his patented low-cost commercial prepa-ration of CD2Cl2 (an excellent NMR solvent) from CH2Cl2/Na2O/D2O.
A detailed study of steric effects on the rotational isomerism and reaction stereochemistry of 9-substituted fluorenes is ongoing. The crystallographic work is being performed by Paul Robinson of our Department of Geology, and computational studies are being carried out by Profs. Howard Dunn and Jeff Seyler of the University of Southern Indiana Department of Chemistry. Pivaloylation of 9-fluorenyllithium with t-Bu(C=O)Cl provided 9-pivaloylfluorene ex-clusively as its ap rotamer in solution (dynamic NMR) and crystalline state. Autoxidation of ap-9-pivaloylfluo-rene via its lithiated 9-anion in MeOH/air ap-pears to proceed with configurational inversion but rotational retention to provide sp-9-hydroxy-9-pivaloylfluorene, veri-fied by X-ray crystallography. While the preferred sp stability of the latter might be associated with intramolecular H-bonding between C=O...HO, it does not account for the preference of the same conformation of 9-methyl-9-pivaloylfluorene. Reduced steric effects of sp vs ap apparently influence both situations. In this same research arena a new type of reaction was recently discovered in this laboratory which superficially constitutes an intramolecular SN2/SN1 double displacement, illustrated below in the conversion of sp-9-(2'-t-butylphenyl)-9-fluorenol (sp-I) to sp-9-[2'-(a,a-dimethyl-b-chloroethyl)phenyl]fluorene (sp-II) by treatment with thionyl chloride. In this reaction Cl- attacks a methyl group displacing an H: which in turn displaces an :OH within the same molecule. From the rotameric structures, proven by X-ray crystallography as shown, this reaction is one of retention of configuration at 9-C. However, the same substrate, sp-I, treated with methanethiol under strongly acidic conditions leads to the formation of ap-9-(2'-t-butylphenyl)-9-methylthiofluorene (ap-III), characterized by X-ray diffraction, shown below, in a reaction which we believe proceeds by inversion of configuration at 9-C.
A cooperative study with Prof. Vera M. Kolb, University of Wisconsin - Parkside, on the reactivity and stereochemistry of urazoles and related compounds was initiated with the observation that urazole nucleosides were formed from the reaction of D-2-deoxyribose with urazole as well as with 4-methylurazole. However, 1-methylurazole was unreactive. The crystalline products from the reactive urazoles were identified by X-ray diffraction as the diastereomeric 1(R),2(R) a-D-2-deoxyribo- pyranosides. The facts that reaction occurred on a hydrazidic N atom and that the substituents on the hydrazidic N atoms are trans disposed suggested that the failure of 1-methylurazole to undergo reaction was due to steric hindrance to attack and/or instability of initial intermediate. Moreover, the surprising chirality of the urazole moiety led us to study the crystal structure of simple urazoles and related compounds. We have found that chirality is an intrinsic structural phenomenon of these compounds in the crystalline state, i.e. that the hydrazidic N atoms are sp3 and their substituents trans juxtaposed, making urazoles and related compounds chiral. These chiral urazoles which have an unsubstituted NH exhibit enantiospecific intermolecular H bonding. The inversion barriers in solution are now being studied.
RECENT PUBLICATIONS/PRESENTATIONS
Meyers, C. Y. Doisynolic-Acid Type Compounds as Weight and Appetite Suppressing and Control Agents. U.S. Patent 5,420,161, 8 claims, May 30, 1995. Abstract: The present invention provides a method of controlling weight and suppressing appetites by administering to an animal, including humans, in need of such treatment, an effective amount of the (+), the (-) or the (+/-) form of a compound shown below, in which R is selected from H, alkyl, alkenyl, benzyl, acyl, and the like. These compounds can be administered as the free carboxylic acid, or as the salt or ester of the carboxylic acid. Furthermore, they may be combined with suitable pharmaceutical carriers for administration.
Meyers, C. Y.; Lutfi, H. G.; Hou, Y.-Q.; and Robinson, P. D. Enantiomer-Selective Intermolecular Hydrogen Bonding in Crystalline Urazoles. Effect on Crystallization Patterns, Melting Points, and Solubilities. American Chemical Society, National Meeting, Chicago, August 20-24, 1995; Abstract No. ORGN 296.
Abstract: An X-ray crystallographic study of urazoles was carried out to investigate the effect of intermolecular H-bonding on the melting points, solubility and crystallization patterns of these structures. The crystal struc- ures of 1-methylurazole (2)*, 4-methylurazole (3), and 1,2,4-trimethylurazole (4) show that their ring atoms and oxygen atoms are essentially coplanar, their imide N atom (N-4) is trigonal, their hydrazide N atoms (N-1, N-2) are pyramidal, and the H atoms/Me groups on N-1, N-2 are trans. Consequently, these urazoles are chiral, and both enantiomers, 1R,2R and 1S,2S, were observed in the respective X-ray crystal structures.
Meyers, C. Y.; Hou, Y.-Q.; Lutfi, H. G.; and Robinson, P. D. 9-Substituted Fluorene Rotomers. Investigation of NMR Spectra, X-Ray Crystal Structure, Reactivities, and Rotational and Configurational Stabilities. American Chemical Society, National Meeting, Chicago, August 20-24, 1995; Abstract No. ORGN 297. ABSTRACT: Fluorenes substituted in the 9-position with a variety of groups have offered a rich arena for the investigation of stable rotamers and their respective chemical and physical characteristics.
Lutfi, H. G., Meyers, C. Y. "Positive Halogen Compounds," chapter in The Chemistry of Functional Groups, Supplement D2, The Chemistry of Halides, Pseudo-halides and Azides,S. Patai and Z. Rappoport, Editors; John Wiley & Sons, London and New York, 1995, pp 1122-1171.
Contents:
I. INTRODUCTION
II. OXYGEN-HALOGEN COMPOUNDS
A. Alkyl Hypohalites
1. Reactions with amines
2. Reactions with alkenes and dienes
B. Acetyl Hypofluorite
C. Miscellaneous Reactions
D. Special Cases
III. NITROGEN-HALOGEN COMPOUNDS
A. N-Haloamides and N-Haloimides
B. N-Fluoro Sulfonamides
C. N-Fluoro Sulfinimides
D. Halogen Azides and Iodine Isocyanate
1. Addition of XN3
2. Addition of iodine isocyanate (IN=C=O)
E. N-Chlorobenzotriazole
F. N-Halo Amines
G. N-Haloammonium Salts
H. Mechanistic Studies of Fluorination with Electrophilic Fluorinating Reagents
IV. CARBON-HALOGEN COMPOUNDS
A. Polyhaloalkanes
1. General
2. Reaction with phosphorous compounds
B. Carbon-halogen Compounds with Electronegative Substitutents (EWG-C-X)
V. SULFUR-HALOGEN COMPOUNDS
The first example of a crystalline urazole nucleoside has been synthesized from the reaction of D-deoxyribose with urazole and characterized by X-ray crystallography as a single a-pyranoside diastereomer [IUPAC name: 1-(2-deoxy-a-D-erythro-pentopyranosyl) 1-(R),2-(R),4-triazolidine-3,5-dione, C7H11N3O5]. The pyranosyl group and H atom on the two pyramidal hydrazidic N atoms have an R, R-trans configuration, and the H atom on the trigonal imidic N atom is coplanar with the ring. Intermolecular hydrogen bonding is extensive and involves pyranose-pyranose, pyranose-urazole, and urazole-urazole interaction. Each molecule is linked via eight hydrogen bonds to six surrounding molecules in which the urazole hydrazidic N(H) atom and imidic N atom are donors and carbonyl O atoms are acceptors, and the pyranose hydroxylic O atoms are donors as well as acceptors; the pyranose-ring O atom does not participate.
Kolb, V. M.; Colloton, P. A.; Robinson, P. D.; Lutfi, H. G. and Meyers, C. Y. (1R,2R)-4,4-dimethylpyrazolidine-3,5-dione-a-D-pyranosyl-2-deoxyriboside. Acta Crystallogr.,1996, C52, 1781-1784.
Abstract:
The first example of a crystalline pyrazolidinedione nucleoside has been synthesized from the reaction of 2-deoxy-D-ribose with 4,4-dimethylpyrazolidine-3,5-dione and characterized by X-ray crystallography as a single a-pyranoside diastereomer [IUPAC name: 1-(2-deoxy-a-D-erythro-pentopyranosyl) 1-(R),2-(R)-4,4-dimethylpyrazolidine-3,5-dione, C10H16N2O5]. Although the pyrazolidinedione ring is essentially planar, the two hydrazidic N atoms are pyramidal and chiral, their respective pyranosyl and H atom substituents being trans-R,R configured. The intermolecular hydrogen bonding involves pyranose-pyranose and pyranose-pyrazolidinedione interactions. Each molecule is linked via six hydrogen bonds to four surrounding molecules in which the pyrazolidinedione hydrazidic N(H) atom is a donor and its adjacent carbonyl O atom is an acceptor, and the pyranose hydroxylic O atoms are donors as well as acceptors. The second carbonyl O atom does not hydrogen bond with OH or NH, but exhibits a weak C-H...O intermolecular interaction with the pyranose ring. The pyranose-ring O atom does not participate in hydrogen bonding. Substituting the OH groups with OD and the NH with ND resulted in no measurable changes in the structure, including hydrogen bonding parameters.
Meyers, C. Y.; Lutfi, H. G.; Kolb, V. M.; Hou, Y.-Q. and Robinson, P. D. Acetone 4,4-
Dimethyl-2-pyrazoline-5-one-3ylhydrazone. Acta Crystallogr., 1996, C52, 2367-2370.
Abstract
The title compound, C8H14N4O, exhibits an overall molecular coplanarity and trigonal planar geometry of all four N atoms, suggesting resonance interaction extending over eight contiguous atoms. Strong hydrogen bonding between hydrazidic N donor and carbonyl O acceptor atoms results in an almost-planar octagonal bridge between two molecules. These dimers are interconnected through a second octagonal bridge of weaker hydrogen bonds between side-chain hydrazine N donor and ring-N acceptor atoms, leading to an almost-flat linear polymeric structure. The acetone-hydrazone N atom does not participate in hydrogen bonding. From the structure of the title compound, the unequivocal identification of 4,4-dimethyl-2-pyrazoline-5-one-3ylhydrazine, an unexpected byproduct of the reaction of 4,4-dimethylpyrazolidine-3,5-dione with hydrazine, was made.
Abstract: The structural, stereochemical and hydrogen-bonding parameters of 4-methylurazole (4-methyl-1,2,4-triazolidine-3,5-dione) (I), C3H5N3O2, were examined in light of its rapid reaction with ribose, and the chirality, high melting points, and resistance to dissolution and crystallization exhibited by related urazoles. Crystalline (I) was found to be composed of two types of racemic molecules with slightly different parameters, [(R,R and S,S)-I-1] and [(R,R and S,S)-I-2]. The ring atoms and O atoms of (I) are essentially coplanar, the imide-N atoms trigonal planar, and hydrazide-N atoms pyramidal with their H atoms trans juxtaposed. An asymmetric cell contains an [(R,R)-I-1] molecule and an [(S,S)-I-2] molecule, or an [(S,S)-I-1] molecule and an [(R,R)-I-2] molecule. A unit cell contains eight molecules: two [(R,R)-I-1], two [(S,S)-I-1], two [(R,R)-I-2] and two [(S,S)-I-2]. In the three-dimensional intermolecular hydrogen-bonding network involving N-H... O=C, a molecule of (I-1) is bridged to four molecules of (I-2), and visa versa, in a diastereospecific pattern. The molecular packing and hydrogen bonding differ considerably from those recently published for (I). Meyers, C. Y.; Lutfi, H. G.; Hou, Y.-Q. and Robinson, P. D. Racemic 1,2,4-Trimethylurazole. Acta Crystallogr., 1996, submitted. Abstract: The structural and stereochemical parameters of 1,2,4-trimethylurazole (1,2,4-trimethyl-1,2,4-triazolidine-3,5-dione) (1), C5H9O2N3, were examined in light of its ease of dissolution and recrystallization in a variety of solvents, ease of sublimation, hygroscopicity, and low melting point, compared with less substituted urazoles. The X-ray structure shows that (1) is devoid of intermolecular hydrogen bonding, but its structural features are remarkably similar to urazoles whose NH functions afford strong intermolecular bonding. Steric repulsion makes the torsion angle of the trans H3C-N-N-CH3, 72.3 (5)ƒ, somewhat larger than the corresponding torsion angles of urazoles whose N-N function is unsubstituted or monomethylated, but not as large as those of urazoles monosubstituted with bulkier groups. Like other crystalline urazoles, (1) is racemic by virtue of N1 and N2 chirality. The packing pattern consists of parallel molecular sheets, with two such sheets passing through the unit cell. Within a sheet each molecule is surrounded by two molecules of its own chirality and four of opposite chirality. This study shows that certain physical properties of crystalline urazoles can be associated with their degree of intermolecular hydrogen bonding, but their chiral properties are intrinsic molecular phenomena which may or may not be affected by hydrogen bonding.