- A mild method for the replacement of a hydroxyl group by halogen. 1. Scope and chemoselectivity
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α-Chloro-, bromo- and iodoenamines, which are readily prepared from the corresponding isobutyramides have been found to be excellent reagents for the transformation of a wide variety of alcohols or carboxylic acids into the corresponding halides. Yields are high and conditions are very mild thus allowing for the presence of sensitive functional groups. The reagents can be easily tuned allowing therefore the selective monohalogenation of polyhydroxylated molecules. The scope and chemoselectivity of the reactions have been studied and reaction mechanisms have been proposed.
- Munyemana, Fran?ois,George, Isabelle,Devos, Alain,Colens, Alain,Badarau, Eduard,Frisque-Hesbain, Anne-Marie,Loudet, Aurore,Differding, Edmond,Damien, Jean-Marie,Rémion, Jeanine,Van Uytbergen, Jacqueline,Ghosez, Léon
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p. 420 - 430
(2015/12/31)
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- Formamides as Lewis Base Catalysts in SNReactions—Efficient Transformation of Alcohols into Chlorides, Amines, and Ethers
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A simple formamide catalyst facilitates the efficient transformation of alcohols into alkyl chlorides with benzoyl chloride as the sole reagent. These nucleophilic substitutions proceed through iminium-activated alcohols as intermediates. The novel method, which can be even performed under solvent-free conditions, is distinguished by an excellent functional group tolerance, scalability (>100 g) and waste-balance (E-factor down to 2). Chiral substrates are converted with excellent levels of stereochemical inversion (99 %→≥95 % ee). In a practical one-pot procedure, the primary formed chlorides can be further transformed into amines, azides, ethers, sulfides, and nitriles. The value of the method was demonstrated in straightforward syntheses of the drugs rac-Clopidogrel and S-Fendiline.
- Huy, Peter H.,Motsch, Sebastian,Kappler, Sarah M.
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supporting information
p. 10145 - 10149
(2016/08/16)
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- Trichloroisocynuric acid/DMF as efficient reagent for chlorodehydration of alcohols under conventional and ultrasonic conditions
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A new and efficient method for the chlorodehydration of alcohols utilizing TCCA/DMF is described. Various alcohols can be converted smoothly into their corresponding alkyl chlorides in high yields under mild conditions with short reaction times. Taylor & Francis Group, LLC.
- Venkana, Purugula,Kumar, Mukka Satish,Rajanna, Kamatala Chinna,Ali, Mir Moazzam
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- Kinetics of the gas-phase elimination reaction of benzyl chloroformate and neopentyl chloroformate
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The gas-phase eliminations of benzyl chloroformate (475-523 K, 31-103 Torr) and neopentyl chloroformate (563-622 K, 37-70 Torr), in a deactivated static reaction vessel, and in the presence of a free radical suppressor, are homogeneous, unimolecular, and follow a first-order rate law. The rate coefficients are expressed by the following Arrhenius equations: Benzyl chloroformate log κI = (13.30 ± 0.38) - (152.9 ± 3.6) kJ mol-1(2.303RT)-1; r = 0.9989 Neopentyl chloroformate Formation of neopentyl chloride: log κI = (14.29 ± 0.48) - (196.3 ± 5.5) kJ mol-1(2.303RT)-1; r = 0.9986 Formation of 2-methylbutenes: log κII = (12.12 ± 0.73) - (178.2 ± 8.3) kJ mol-1(2.303RT)-1; r = 0.9960 The derived kinetic and thermodynamic parameters for benzyl chloroformate decomposition indicate the reaction proceeds through a concerted four-membered cyclic transition state to give benzyl chloride and CO2 gas. Neopentyl chloroformate undergoes a parallel reaction, where neopentyl chloride formation may arise from a polar-concerted four-membered cyclic transition state, whereas the mixture of olefins, 2-methyl-2-butene, and 2-methyl-1-butene appears to be produced from a carbene intermediate. This intermediate seems to be originated from a concerted five-membered cyclic transition state of the neopentyl substrate.
- Lezama, Jesus,Domnguez, Rosa M.,Chuchani, Gabriel
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p. 104 - 112
(2015/04/22)
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- C-HALOGEN BOND FORMATION
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Methods of halogenating a carbon containing compound having an sp3 C-H bond are provided. Methods of fluorinating a carbon containing compound comprising halogenation with Cl or Br followed by nucleophilic substitution with F are provided. Methods of direct oxidative C-H fluorination of a carbon containing compound having an sp3 C-H bond are provided. The halogenated products of the methods are provided.
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Paragraph 0111-0118
(2013/03/26)
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- Manganese porphyrins catalyze selective C-H bond halogenations
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We report a manganese porphyrin mediated aliphatic C-H bond chlorination using sodium hypochlorite as the chlorine source. In the presence of catalytic amounts of phase transfer catalyst and manganese porphyrin Mn(TPP)Cl 1, reaction of sodium hypochlorite with different unactivated alkanes afforded alkyl chlorides as the major products with only trace amounts of oxygenation products. Substrates with strong C-H bonds, such as neopentane (BDE =~100 kcal/mol) can be also chlorinated with moderate yield. Chlorination of a diagnostic substrate, norcarane, afforded rearranged products indicating a long-lived carbon radical intermediate. Moreover, regioselective chlorination was achieved by using a hindered catalyst, Mn(TMP)Cl, 2. Chlorination of trans-decalin with 2 provided 95% selectivity for methylene-chlorinated products as well as a preference for the C2 position. This novel chlorination system was also applied to complex substrates. With 5α-cholestane as the substrate, we observed chlorination only at the C2 and C3 positions in a net 55% yield, corresponding to the least sterically hindered methylene positions in the A-ring. Similarly, chlorination of sclareolide afforded the equatorial C2 chloride in a 42% isolated yield. Regarding the mechanism, reaction of sodium hypochlorite with the MnIII porphyrin is expected to afford a reactive MnVO complex that abstracts a hydrogen atom from the substrate, resulting in a free alkyl radical and a MnIV-OH complex. We suggest that this carbon radical then reacts with a MnIV-OCl species, providing the alkyl chloride and regenerating the reactive MnVO complex. The regioselectivity and the preference for CH2 groups can be attributed to nonbonded interactions between the alkyl groups on the substrates and the aryl groups of the manganese porphyrin. The results are indicative of a bent [MnvO-H-C] geometry due to the C-H approach to the MnvO (dπ-pπ)* frontier orbital.
- Liu, Wei,Groves, John T.
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supporting information; experimental part
p. 12847 - 12849
(2010/11/05)
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- Isomerization of neopentyl chloride and neopentyl bromide by a 1,2-Interchange of a halogen atom and a methyl group
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The recombination of chloromethyl and t-butyl radicals at room temperature was used to generate neopentyl chloride molecules with 89 kcal mol-1 of internal energy. The observed unimolecular reactions, which give 2-methyl-2-butene and 2-methyl-1-butene plus HCl, as products, are explained by a mechanism that involves the interchange of a methyl group and the chlorine atom to yield 2-chloro-2-methylbutane, which subsequently eliminates hydrogen chloride by the usual four-centered mechanism to give the observed products. The interchange isomerization process is the rate-limiting step. Similar experiments were done with CD2Cl and C(CH3)3 radicals to measure the kinetic-isotope effect to help corroborate the proposed mechanism. Density functional theory was employed at the B3PW91/6-31G(d',p') level to verify the Cl/CH3 interchange mechanism and to characterize the interchange transition state. These calculations, which provide vibrational frequencies and moments of inertia of the molecule and transition state, were used to evaluate the statistical unimolecular rate constants. Matching the calculated and experimental rate constants, gave 62 ± 2 kcal mol -1 as the threshold energy for interchange of the Cl atom and a methyl group. The calculated models also were used to reinterpret the thermal unimolecular reactions of neopentyl chloride and neopentyl bromide. The previously assumed Wagner-Meerwein rearrangement mechanism for these reactions can be replaced by a mechanism that involves the interchange of the halogen atom and a methyl group followed by HCl or HBr elimination from 2-chloro- 2-methylbutane and 2-bromo-2-methylbutane. Electronic structure calculations also were done to find threshold energies for several related molecules, including 2-chloro-3,3-dimethylbutane, 1-chloro-2-methyl-2-phenylpropane, and 1-chloro-2-methyl-2-vinylpropane, to demonstrate the generality of the interchange reaction involving a methyl, or other hydrocarbon groups, and a chlorine atom. The interchange of a halogen atom and a methyl group located on adjacent carbon atoms can be viewed as an extension of the halogen atom interchange mechanisms that is common in 1,2-dihaloalkanes.
- Lisowski, Carmen E.,Duncan, Juliana R.,Ranieri, Anthony J.,Heard, George L.,Setser,Holmes, Bert E.
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scheme or table
p. 10395 - 10402
(2011/02/18)
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- An efficient route to alkyl chlorides from alcohols using the complex TCT/DMF
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(formula presented) Efficient conversion of alcohols and β-amino alcohols to the corresponding chlorides (and bromides) can be carried out at room temperature in methylene chloride, using 2,4,6-trichloro[1,3,5]triazine and N,N-dimethyl formamide. This procedure can also be applied to optically active carbinols.
- De Luca, Lidia,Giacomelli, Giampaolo,Porcheddu, Andrea
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p. 553 - 555
(2007/10/03)
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- Reinvestigation of the SNi Reaction. The Ionization of Chlorosulfites
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The decomposition of alkyl chlorosulfites (ROSOCl) has been investigated both computationally and experimentally.Semiempirical (AM1 and PM3) as well as ab initio (HF/3-21G(*), HF/6-31G*, and MP2(full)/6-31G*//MP2(full)/6-31G*) methods were employed, and the results were confirmed experimentally by NMR spectroscopy.The computations indicated that certain alkyl sulfinyl cations (ROSO(1+)) are stable and might be involved in the decomposition of chlorosulfites.Detection of these ions by 1H and 13C NMR spectroscopy in polar solvents such as acetone-d6 and acetonitrile-d3 as well as kinetic studies allowed important conclusions to be drawn about the mechanistic details of the SNi reaction.We conclude that primary alkyl chlorosulfites ionize to yield a sulfinyl cation (ROSO(1+)) and Cl(1-), whereas tertiary chlorosulfites preferentially give a carbenium ion and a chlorosulfinyl anion (OSOCl(1-)) The generation of these ion pairs is facilitated in polar solvents where the rates of decomposition of chlorosulfites are largely accelerated.The decomposition of neopentyl chlorosulfite without rearrangement and the substitution at the bridgehead position of 7,7-dimethylbicycloheptyl 1-chlorosulfite show that the loss of SO2 from ROSO(1+) must be accompanied by the attack of the chloride ion from the front side.
- Schreiner, Peter R.,Rague Schleyer, Paul von,Hill, Richard K.
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p. 2822 - 2829
(2007/10/02)
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- REGIOSELECTIVE REPLACEMENT OF THE HYDROXY GROUP IN ALCOHOLS BY MEANS OF TRIHALOACETIC DERIVATIVES IN PRESENCE OF TRIPHENYLPHOSPHINE
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The investigation of the reactions of trichloroacetonitrile with 2-decanol, 2-methyl-3-octanol, 2,4-dimethyl-3-pentanol, and 2,2-dimethyl-1-propanol in presence of triphenylphosphine shows that the formation of alkyl chlorides from the corresponding alcohols goes regiospecifically: Even for 2,4-dimethyl-3-pentanol the amount of the isomeric chloride does not exceed 1percent, while neopentyl alcohol is converted into neopentyl chloride in 95percent yield.On the introduction of "external" nucleophiles (iodide and thiocyanate ions) into the reaction mixture the predominating reaction product is the alkyl chloride.As a result of the reaction of bromotrichloromethane with 1-nonanol and triphenylphosphine a mixture of the alkyl chloride and the alkyl bromide is formed.
- Matveeva, E. D.,Yalovskaya, A. I.,Cherepanov, I. A.,Bundel', Yu. G.,Kurts, A. L.
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p. 1409 - 1415
(2007/10/02)
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- Viscosity-dependent cage reactions. Multiple substitutions in radical-chain chlorinations
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The mechanism by which the free-radical chlorination of alkanes produces polychlorides has been explained by the assumption that the geminate chlorine atom-chloroalkane pair react in their solvent cage at rates competitive with their diffusion from, and rotation in, the cage in which they are born. The major piece of evidence supporting this mechanism is that as the concentration of alkane is increased, polyhalogenation decreases. As the hydrocarbon that makes up the "cage walls" becomes more concentrated, the surrounding hydrocarbon scavenges the caged chlorine atoms before they react with their geminate chloroalkane. In the inert solvents in which these reactions take place, CCl4 or various Freons, the viscosity of the solvent is decreased with increasing concentration of hydrocarbon, and the diffusion rates are therefore increased. The diffusion dependence (i.e., viscosity) of the amount of polychlorination is an important component of the observed concentration dependence. The influence of the changing viscosity upon the production of polychlorination becomes more important as the hydrocarbon (neopentane, 2,3-dimethylbutane, or cyclohexane) makin up the cage walls becomes less reactive. The viscosity dependence of cage rotation was observed in solvents of high viscosity for the least reactive hydrocarbon, neopentane.
- Tanner, Dennis D.,Oumar-Mahamat,Meintzer, Christian P.,Tsai, Eve C.,Lu, Thanh T.,Yang, Dilun
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p. 5397 - 5402
(2007/10/02)
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- Gas-phase SN2 and E2 reactions of alkyl halides
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Rate coefficients have been measured for the gas-phase reactions of methyl, ethyl, n-propyl, isopropyl, tert-butyl, and neopentyl chlorides and bromides with the following set of nucleophiles, listed in order of decreasing basicity: HO-, CH3O-, F-, HO- (H2O), CF3CH2O-, H2NS-, C2F5CH2O-, HS-, and Cl-. For methyl chloride the reaction efficiency first falls significantly below unity with HO- (H2O) as the nucleophile and for methyl bromide with HS- as the nucleophile; in both cases the overall reaction exothermicity is about 30 kcal mol-1. Earlier conclusions that these halides react slowly with stronger bases are shown to be in error. In the region where the rates are slow oxygen anions react with the alkyl chlorides and bromides by elimination while sulfur anions of the same basicity react by substitution. This difference is due to a slowing down of elimination with the sulfur bases; sulfur anions show no increased nucleophilicity as compared to oxy anions of the same basicity. Rate coefficients have also been measured for reaction of methyl fluoride with HO- and CH3O- and ethylene oxide with HO-, CH3O-, and F-. All of these rates are slow but measurable; combining the results of these experiments with those of the alkyl chlorides and bromides suggests that the gas-phase barrier to the symmetrical SN2 reaction of F- with methyl fluoride is lower than previous estimates. We have also measured rates for reaction of allyl chloride with F-, H2NS-, and HS-, chloromethyl ether with H2NS- and HS-, chloroacetonitrile with F-, H2NS-, HS-, and 37Cl-, bromoacetonitrile with Cl- and 81Br-, and α-chloroacetone with H2NS-, HS-, and 37Cl-. Our results also imply that the gas-phase SN2 barrier for Br- reacting with methyl bromide is nearly equal to the ion-dipole attraction energy of the reactants, in agreement with previous estimates.
- DePuy, Charles H.,Gronert, Scott,Mullin, Amy,Bierbaum, Veronica M.
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p. 8650 - 8655
(2007/10/02)
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- PREPARATION OF ALKYL-ARYL ETHERS AND THIOETHERS
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A method, which involves no molecular rearrangement, and which is also stereospecific, for the preparation of alkyl-aryl ethers and thioethers is described.Stable alkoxyphosphonium salts, R-O-P(1+)(NMe2)3 PF6(1-), have been prepared and treated with phenols and thiophenols, under basic conditions, to yield the corresponding alkyl-aryl ethers and thioethers respectively.
- Downie, Ian M.,Heaney, Harry,Kemp, Graham
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p. 2619 - 2624
(2007/10/02)
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- REACTIONS OF BrCl WITH ALKYL RADICALS.
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It is demonstrated that photohalogenation of low reactivity substrates with BrCl occurs mainly with Cl. selectivity.With tertiary or benzylic hydrogens in the substrate, mainly Br. selectivity is observed.These observations are rationalized, taking into account the relative concentrations of halogen atoms and their respective rates of hydrogen abstractions.The resultant radicals react with BrCl to make (RBr/RCl) in ratios between 1 and 15.
- Skell, P. S.,Baxter, H. N.,Tanko, J. M.
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p. 5181 - 5184
(2007/10/02)
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- Chlorine Atom/Benzene System. 1. The Role of the 6-Chlorocyclohexadienyl Radical
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The concept of radical reactivity mediated by solvation has rested mainly on the alteration of Cl. properties by aromatic solvents.For this reason, the full scope of the benzene/Cl. system has been reexamined to evaluate the discription of that system based largely on a ?-complex (solvation).At the present time, the ?-complex description rests narrowly on the assignment of a 490-nm absorption, which, even if correct, could not provide an unambiguous structure assignment.Results are presenteed which described the selectivities in alkane substitutions as a function of the concentrations of both benzene and the alkane.Selectivities increase with decreasing alkane concentrations, reaching a plateau below 0.1 M alkane.The change in selectivity is the result of variable contributions of both a low- and a high-selectivity intermediate, LSI and HSI, respectively.The observed selectivity at a given and is the consequence of a unique / ratio.A range of substrates and their effect of DMB selectivity were studied, and from these results details regarding the chemistry of the HSI were extracted.Several features of the LSI/HSI equilibrating system are realized. (1) Reaction of alkyl radicals with Cl2 in benzene produces the LSI, (2) the LSI does not exhibit the characteristics of free chlorine atom, and (3) at alkane concentrations and , added reagents (T) which react with CCH, such as maleic anhydride (MA) or Cl2, bring about an increase in the LSI/HSI ratio.Low-selectivity hydrogen abstractions (LSI function) are best ascribed to a mixture of chlorine atom and chlorine atom/benzene ?-complex.The chemistry of CCH is as follows: (1) loss of the ipso H to O2 yielding PhCl and HO2., (2) reactions of Cl2 or (3) maleic anhydride with the aromatic nucleus of CCH resulting in additions to the ring, (4) the transfer of Cl to alkenes, and (5) the highly selective retardation of rates of reaction with alkanes producing alkyl radicals, HCl, and benzene.The results of a kinetic analysis, accounting for the effect of , , and CCH trapping agents (T), are presented.For CCH, the following reactivity order is established: maleic anhydride (6) > trans-dichloroethene(5) > 2,3-dimethylbutane (2) > pentane (1) > Cl2 > neopentane ( 2 (27) > 1 .These properties can be rationalized with canonical structures for CCH wherein spin density at carbon, chlorine, and the ipso hydrogen makes contributions to the hybrid.
- Skell, Philip S.,Baxter, Harry N.,Tanko, James M.,Chebolu, Venkatasuryanarayana
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p. 6300 - 6311
(2007/10/02)
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- Quasiphosphonium Intermediates. Part 3. Preparation, Structure, and Reactivity of Alkoxyphosphonium Halides in the Reaction of Neopentyl Diphenylphosphinite, Dineopentyl Phenylphosphinite, and Trineopentyl Phosphite with Halogenomethanes and the Effect of Phenoxy-substituenst on the ...
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The reactions of neopenthyl diphenylphosphinite with chloro-, bromo-, or iodo-methane and of dineopentyl phenylphosphphonite with bromo- or iodo-methane yield crystalline alkoxyphosphonium halides.In deuteriochloroform these intermediates decompose by a first-order process which involves rate-determining collapse of the phosphonium halide ion-pair with SN2-type fission of the alkyl-oxygen bond.Rates for chloride, bromide, and iodide are similar.In a more ionising medium (deuterioacetonitrile) dissociation leads to stabilisation of the intermediates and to deviation from first-order decomposition.Previously determined X-ray diffraction data for the bromides, together with relative rates of decomposition in deuteriochloroform for intermediates in the series Phn(RO)3-nP+MeX- (n = 0,1, or 2) suggest that the stability and reactivity of alkoxyphosphonium intermediates are determined largely by inductive rather than mesomeric effects of ligands.The presence of phenoxy-substituents on phosphorus may cause a tendency towards SN1-type fission of the alkyl-oxygen bond in certain circumstances.
- Hudson, Harry R.,Kow, Aloysius,Roberts, John C.
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p. 1363 - 1368
(2007/10/02)
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- Pyrylium Mediated Transformations of Neopentylamine
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A series of 2,4-diphenyl-5,6-dihydrobenzochromenylium salts have been prepared.They react with neopentylamine to form the corresponding 1-neopentylquinolinium salts which on thermolysis afford neopentyl halides, trifluoracetate, and thiocyanate, in good yields without rearrangements.
- Katritzky, Alan R.,Singh, Jagadish N.
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p. 421 - 424
(2007/10/02)
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- Pyrolytic Eliminations from N,N-Dichloro Derivatives of Primary, Secondary, and Tertiary Alkyl Primary Amines
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N,N-Dichloro derivatives of primary, secondary, and tertiary alkyl primary amines are easily converted to elimination products by neat or solution pyrolysis during GLC at 190-280 deg C.Good to excellent yields result.In general, the type of product formed depends on the alkyl group: with primary alkyl, the products are alkenes and nitriles; with secondary, alkenes and chloroimines result; and with tertiary types, alkenes are formed.Mechanistic aspects are treated.
- Roberts, John T.,Rittberg, Barry R.,Kovacic, Peter
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p. 4111 - 4115
(2007/10/02)
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- Mechanism of the Triphenylphosphine-Tetrachloromethane-Alcohol Reaction: Pericyclic or Clustered Ion Pairs?
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The intermediate formed from tetrachloromethane-triphenylphosphine and neopentyl alcohol decomposes bimolecularly in acetonitrile and not unimolecularly as in CDCl3.This kinetic order is not consistent with a pericyclic pathway but is consistent with an ion-pair mechanism.Consistent with the ion-pair mechanism in acetonitrile is the incorporation of external nucleophiles in the neopentyl skeleton by addition of added nucleophiles to the system.Consistent with the enhanced polarity of acetonitrile is the increased amount of carbon-oxygen cleavage resulting in extensive racemization of the reaction product from (R)-(+)-2-octanol.The preparation of neopentyl thiocyanate and neopentyl isothiocyanate from the corresponding alcohol illustrates the synthetic utility of this reaction in more polar solvents.
- Slagle, J. D.,Huang, T. T.-S.,Franzus, B.
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p. 3526 - 3530
(2007/10/02)
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- Arbuzov Reaction of Alkyl and Silyl Phosphites with Halogens involving Four- and Five-co-ordinate Intermediates
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Low temperature 31P n.m.r. spectroscopy and chemical data have been applied to elucidate the mechanism of the Arbuzov-type reaction between phosphites and halogens.Simple and substituted trialkyl, alkyl 1,2-phenylene, and trisilyl phosphites have been allowed to react with chlorine, bromine, and iodine.In some cases intermediate halogenophosphonium salt (2) and in others halogenophosphoranes (3) are observed which then decompose into the corresponding pure highly reactive phosphorohalidates (4).It was possible to prepare stable phosphonium salts from halogenophosphonium salts (2) and halogenophosphoranes (3).
- Michalski, Jan,Pakulski, Marek,Skowronska, Aleksandra
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p. 833 - 836
(2007/10/02)
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- Thermolysis of N,N-Dihalo Derivatives of Bridgehead and Neopentylamines to the Corresponding Halides.
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N,N-Dihalo derivatives of (1-adamantyl)- and neopentylamine are converted to the corresponding alkyl halides in excellent yields (88-94percent) during GLC at 155-330 deg C.Decomposition apparently occurs by an SNi mechanism or by intramolecular homolytic cleavage.Intermolecular radical and free-ion reactions are eliminated from consideration because of the absence of radical-derived or rearranged products.Steric factors are deemed important in the neopentyl case since pyrolysis of N,N-dihaloamine gave the corresponding carbonitrile in excellent yield(90-97percent). 1-(Haloamino)adamantanes gave fair amounts of 1-haloadamantanes (30-38percent). 1-(Acetylamino)- and 1-(ethylchloroamino)adamantane yielded 1-chloroadamantane (10-17percent), the major products being the acetamide (60percent) and the ethylamine (56percent), respectively. 1-(Dihaloamino)adamantanes were converted to 1-haloadamantanes by neat (64-70percent) or solution (30-41percent) pyrolysis.
- Roberts, John T.,Rittberg, Barry R.,Kovacic, Peter,Scalzi, Francis V.,Seely, Michael J.
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p. 5239 - 5243
(2007/10/02)
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