- An unusual ligand coordination gives rise to a new family of rhodium metalloinsertors with improved selectivity and potency
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Rhodium metalloinsertors are octahedral complexes that bind DNA mismatches with high affinity and specificity and exhibit unique cell-selective cytotoxicity, targeting mismatch repair (MMR)-deficient cells over MMR-proficient cells. Here we describe a new generation of metalloinsertors with enhanced biological potency and selectivity, in which the complexes show Rh-O coordination. In particular, it has been found that both δ- and -[Rh(chrysi)(phen)(DPE)]2+ (where chrysi =5,6 chrysenequinone diimmine, phen =1,10-phenanthroline, and DPE = 1,1-di(pyridine-2-yl)ethan-1-ol) bind to DNA containing a single CC mismatch with similar affinities and without racemization. This is in direct contrast with previous metalloinsertors and suggests a possible different binding disposition for these complexes in the mismatch site. We ascribe this difference to the higher pKa of the coordinated immine of the chrysi ligand in these complexes, so that the complexes must insert into the DNA helix with the inserting ligand in a buckled orientation; spectroscopic studies in the presence and absence of DNA along with the crystal structure of the complex without DNA support this assignment. Remarkably, all members of this new family of compounds have significantly increased potency in a range of cellular assays; indeed, all are more potent than cisplatin and N-methyl-N'-nitro-nitrosoguanidine (MNNG, a common DNA-alkylating chemotherapeutic agent). Moreover, the activities of the new metalloinsertors are coupled with high levels of selective cytotoxicity for MMR-deficient versus proficient colorectal cancer cells.
- Komor, Alexis C.,Barton, Jacqueline K.
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- A Journey through Hemetsberger–Knittel, Leimgruber–Batcho and Bartoli Reactions: Access to Several Hydroxy 5- and 6-Azaindoles
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The preparation of various 5- and 6-azaindoles, heterocyclic structures that are frequently part of molecules in clinical development, and their monohydroxy analogues were described. Different strategies, relying on the de novo pyrrole ring formation, were investigated and, thanks to Hemetsberger–Knittel, Bartoli and Leimgruber–Batcho approaches, 4- and 7-monohydroxy 5- and 6-azaindoles were obtained. The crucial introduction of the oxygen atom was carried out from halogen derivatives, using nucleophilic substitution reactions under basic conditions with or without a copper catalyst. Some preliminary oxidation reactions have shown that it was yet not possible to synthesize the azaquinone indole structure from monohydroxy azaindole, using molecular oxygen in the presence of salcomine as a catalyst.
- Radix, Sylvie,Hallé, Fran?ois,Mahiout, Zahia,Teissonnière, Amélie,Bouchez, Grégoire,Auberger, Ludovic,Barret, Roland,Lomberget, Thierry
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- Green synthesis method of polyaryl substituted methanol
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The invention relates to a green synthesis method of polyaryl substituted methanol, in particular to a method for efficiently synthesizing polyaryl substituted methanol in a polar aprotic solvent under the condition of an oxidizing agent by taking polyaryl substituted methane as a raw material and alkali as an additive. The method provided by the invention is green and environment-friendly, avoids using expensive metal catalysts, and has the advantages of low cost, few reaction steps, short time, high yield and the like.
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Paragraph 0127-0136
(2021/04/17)
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- Mild Condition for the Deoxygenation of α-Heteroaryl-Substituted Methanol Derivatives
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A mild condition via PPh3/I2/imidazole for the deoxygenation of substituted methanol derivatives has been identified. This metal-free process was found to proceed well on secondary or tertiary alcohols substituted with one or two heteroaryl groups, and it tolerates acid-sensitive heterocycles. This condition works for methanol derivatives substituted with 2-pyridyl, 4-pyridyl, or other heterocyclic groups, allowing the negative charge formed during the reaction to resonate to a nitrogen atom. Methanol derivatives substituted with 3-pyridyl or heterocyclic groups that do not allow the negative charge formed during the reaction to resonate to a nitrogen atom will not undergo deoxygenation under this condition.
- Meng, Na,Yu, Wensheng,Suzuki, Takao,Chen, Maofen,Qi, Zhiqi,Hu, Bin,Bao, Jianming,Debenham, John S.,Mazzola, Robert,Duffy, Joseph L.
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p. 5560 - 5567
(2021/05/04)
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- Transition-Metal Free Chemoselective Hydroxylation and Hydroxylation-Deuteration of Heterobenzylic Methylenes
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We developed an approach for direct selective hydroxylation of heterobenzylic methylenes to secondary alcohols avoiding overoxidation to ketones by using a KOBu-t/DMSO/air system. Most reactions could reach completion in several minutes to give hydroxylated products in 41-76% yields. Using DMSO-d6, this protocol resulted in difunctionalization of heterobenzylic methylenes to afford α-deuterated secondary alcohols (>93% incorporation). By employing this method, active pharmaceutical ingredients carbinoxamine and doxylamine were synthesized in two steps in moderate yields.
- Fu, Yiwei,Li, Hao,Liu, Yonghai,Mang, Zhiguo,Shi, Lei,Sun, Chengyu,Yu, Yang
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supporting information
p. 8127 - 8131
(2020/11/03)
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- Difunctionalization of Alkenylpyridine N-Oxides by the Tandem Addition/Boekelheide Rearrangement
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A convenient and efficient approach for the difunctionalization of alkenylpyridine N-oxides through the tandem addition/Boekelheide rearrangement has been developed. The C-O and C-X (S, O, Cl) bonds are constructed simultaneously at the α- and β-positions under mild reaction conditions in 100% atom economy, which complements previously reported α- or β-functionalizations.
- Xun, Xudong,Zhao, Man,Xue, Jianzhong,Hu, Tao,Zhang, Ming,Li, Guofeng,Hong, Liang
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supporting information
p. 8266 - 8269
(2019/10/16)
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- Iron-Catalyzed Aerobic Oxidation of (Alkyl)(aryl)azinylmethanes
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An iron-catalyzed aerobic oxidation of (alkyl)(aryl)azinylmethanes has been developed leading to tertiary alcohols in moderate to good yields. Hock rearrangement was identified as a major side reaction leading to a complex mixture of undesired products. Addition of thiourea sometimes allows inhibiting this side reaction and steers the reaction towards the desired products.
- Sterckx, Hans,Sambiagio, Carlo,Lemière, Filip,Tehrani, Kourosch Abbaspour,Maes, Bert U. W.
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p. 1564 - 1570
(2017/08/11)
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- β-Selective Reductive Coupling of Alkenylpyridines with Aldehydes and Imines via Synergistic Lewis Acid/Photoredox Catalysis
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Umpolung (polarity reversal) strategies of aldehydes and imines have dramatically expanded the scope of carbonyl and iminyl chemistry by facilitating reactions with non-nucleophilic reagents. Herein, we report the first visible light photoredox-catalyzed β-selective reductive coupling of alkenylpyridines with carbonyl or iminyl derivatives with the aid of a Lewis acid co-catalyst. Our process tolerates complex molecular scaffolds (e.g., sugar, natural product, and peptide derivatives) and is applicable to the preparation of compounds containing a broad range of heterocyclic moieties. Mechanistic investigations indicate that the key step involves single-electron-transfer reduction of aldehydes or imines followed by the addition of resulting ketyl or α-aminoalkyl radicals to Lewis acid-activated alkenylpyridines.
- Lee, Katarzyna N.,Lei, Zhen,Ngai, Ming-Yu
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supporting information
p. 5003 - 5006
(2017/05/04)
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- A method for preparing many west pulls sensitively succinic acid
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The invention relates to a preparation method of doxylamine succinate. The preparation method comprises the steps as follows: firstly, a Grignard reagent generated by iodobenzene and magnesium reacts with 2-acetylpyridine to generate 2-pyridyl phenyl methyl alcohol, the 2-pyridyl phenyl methyl alcohol is recrystallized to be purified, then the 2-pyridyl phenyl methyl alcohol reacts with sodium amide and 2-dimethylamino chloroethane sequentially, doxylamine is obtained and has a salt forming reaction with succinic acid finally, and the doxylamine succinate is obtained. The preparation method is high in reaction efficiency, lower in cost and applicable to industrial mass production.
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Paragraph 0032-0034
(2017/03/08)
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- PBr3-mediated unexpected reductive deoxygenation of α-aryl-pyridinemethanols: Synthesis of arylmethylpyridines
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PBr3-mediated reductive deoxygenation of α-aryl-pyridinemethanols to provide arylmethylpyridines is described, the alcohol substrate scope is explored, free radical trap TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy) is introduced, and the hydrogen source of the methylene product is defined. The unexpected reaction enabled us to prepare previously inaccessible, novel EP1 antagonists.
- Nishigaya, Yosuke,Umei, Kentaro,Watanabe, Daisuke,Kohno, Yasushi,Seto, Shigeki
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supporting information
p. 1566 - 1572
(2016/03/01)
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- Zn(salen)-catalyzed enantioselective phenyl transfer to aldehydes and ketones with organozinc reagent
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Abstract A chiral zinc complex of salen was found to be an efficient catalyst for the phenyl transfer of organozinc reagent to aromatic aldehydes and ketones. High enantioselectivities were obtained in reactions of both aromatic aldehydes and ketones (up to 97% and 92% ee, respectively).
- Shimizu, Keisuke,Uetsu, Hidenori,Gotanda, Takashi,Ito, Katsuji
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p. 1238 - 1242
(2015/03/31)
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- Manganese-Catalyzed Direct Nucleophilic C(sp2)-H Addition to Aldehydes and Nitriles
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Herein, a manganese-catalyzed nucleophilic addition of inert C(sp2)-H bonds to aldehydes and nitriles is disclosed by virtue of a dual activation strategy. The reactions feature mild reaction conditions, excellent regio- and stereoselectivity, and a wide substrate scope, which includes both aromatic and olefinic C-H bonds, as well as a large variety of aldehydes and nitriles. Moreover, mechanistic studies shed light on possible catalytic cycles.
- Zhou, Bingwei,Hu, Yuanyuan,Wang, Congyang
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supporting information
p. 13659 - 13663
(2015/11/16)
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- METALLOINSERTOR COMPLEXES TARGETED TO DNA MISMATCHES
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A composition including a Rh or Ru metailoinsertor complex specifically targets mismatch repair (MMR)~deficient cells. Selective cytotoxicity is induced in MMR-deficient cells upon uptake of the inventive metailoinsertor complexes.
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Paragraph 00151
(2015/01/09)
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- [1,2]-Wittig rearrangement of aromatic heterocycles
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Anionic rearrangement of diverse heteroaryl ethers is reported. In many cases, directed metallation followed by formal [1,2]-Wittig rearrangement provides heteroaryl carbinols in good yield.
- Yang, Jingyue,Wangweerawong, Apiwat,Dudley, Gregory B.
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p. 1603 - 1606
(2012/08/29)
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- Synthesis and crystal structures of α-phenyl- and α-trifluoromethyl-α-(2-pyridyl-N-oxide)ethanols and α-phenyl-α-(2-pyridyl-N-oxide)ethylene
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The X-ray structures of two α-substituted α-(2-pyridyl-N-oxide) ethanols, the α-phenyl- (3a) and α-trifluoromethyl- (3b) derivatives, were determined. On dehydration of 3a, compound 4a was obtained. This study brought a clear proof that the α-(2-pyridyl-N-oxide)ethanols are formed following oxidation with peroxides of their corresponding pyridines. A different molecular packing was observed for the α-trifluoromethyl derivative due to an additional hydrogen bonding. Compound 3a crystallized in the monoclinic space group P 21/n with unit cell parameters a = 5.7416(1) A, b = 14.3841(4) A, c = 13.2821(3) A, β = 94.918(2)°, V = 1092.90(4) A3, Z = 4, D = 1.308 Mg/m 3. Compound 3b crystallized in the triclinic space group P -1 with unit cell parameters a = 6.1209(2) A, b = 8.1938(4) A, c = 9.4675(4) A, α = 73.363(3)°, β = 73.166(3)°, γ = 71.659(3)°, V = 421.32(3) A3, Z = 2, D = 1.633 Mg/m 3. Compound 4a crystallized in the monoclinic space group P 2 1/n with unit cell parameters a = 9.3579(3) A, b = 12.7340(3) A, c = 9.8579(3) A, β = 117.3249(15)°, V = 1043.63(5) A3, Z = 4, D = 1.255 Mg/m3.
- Modec, Barbara,Stephan, Michel
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scheme or table
p. 386 - 390
(2011/10/17)
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- [1,2]-Anionic rearrangement of 2-benzyloxypyridine and related pyridyl ethers
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(Chemical Equation Presented) An anionic rearrangement of 2-benzyloxypyridine is described. Pyridine-directed metalation of the benzylic carbon leads to 1,2-migration of pyridine via a postulated associative mechanism (addition/elimination). Several aryl pyridyl carbinols were obtained in high yields. A formal synthesis of carbinoxamine, an antihistamine drug used for the treatment of seasonal allergies and hay fever, emerges from this methodology.
- Yang, Jingyue,Dudley, Gregory B.
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supporting information; experimental part
p. 7998 - 8000
(2010/03/01)
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- Synthesis and activity studies of analogues of the rat selective toxicant norbormide
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Norbormide [5-(α-hydroxy-α-2-pyridylbenzyl)-7-(α-2-pyridylbenzylidene)-5-norbornene-2,3-dicarboximide] (NRB, 1), an existing but infrequently used rodenticide, is known to be uniquely toxic to rats but relatively harmless to other rodents and mammals. A series of NRB-related analogues were prepared to investigate the structural features responsible for, and the in vitro biological markers indicative of, in vivo lethality of the parent molecule in rats. Their synthesis and biological evaluation (vasoconstriction, vasodilation, mitochondrial dysfunction, cardiotoxicity and lethality) is described.
- Rennison, David,Bova, Sergio,Cavalli, Maurizio,Ricchelli, Fernanda,Zulian, Alessandra,Hopkins, Brian,Brimble, Margaret A.
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p. 2963 - 2974
(2008/02/01)
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- Naphthalene-catalysed lithiation of chlorinated nitrogenated aromatic heterocycles and reaction with electrophiles
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Naphthalene catalysed reductive lithiation of various chloroazines (1, 7, 10, 13) in the presence of different electrophiles yields, after hydrolysis, the expected functionalised heterocycles with one (2, 8), two (11, 14a-d) and three nitrogen atoms in the ring (14e,f). This methodology allowed us to trap in situ the lithium imine derived from the reaction of 2- pyridyllithium with benzonitrile, by reaction with a Grignard reagent in the presence of titanium alkoxides. 2,4-Dimethoxypyrimidines (14a,c,d) are demethylated under acidic conditions to give the corresponding uracil derivatives 16. (C) 2000 Elsevier Science Ltd.
- Gómez, Inmaculada,Alonso, Emma,Ramón, Diego J.,Yus, Miguel
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p. 4043 - 4052
(2007/10/03)
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- Highly asymmetric dihydroxylation of 1-aryl-1'-pyridyl alkenes
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The asymmetric dihydroxylation of 1-aryl-1'-pyridyl alkenes afforded the diols in high yield and excellent enantioselectivity. (C) 2000 Published by Elsevier Science Ltd.
- Wang, Xin,Zak, Mark,Maddess, Mathew,O'Shea, Paul,Tillyer, Richard,Grabowski,Reider, Paul J.
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p. 4865 - 4869
(2007/10/03)
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- 85. Development of Luminescent Europium(III) and Terbium(III) Chelates of 2,2':6',2''-Terpyridine Derivatives for Protein Labelling
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The synthesis and luminescence properties are reported for 20 different chelates composed of 2,2':6',2''-terpyridine as the energy-absorbing and donating group, Eu(III) and Tb(III) as the emitting ions, methylenenitrilo(acetic acids) as the stable chelate
- Mukkala, Veli-Matti,Helenius, Matti,Hemmilae, Ilkka,Kankare, Jouko,Takalo, Harri
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p. 1361 - 1378
(2007/10/02)
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- PREPARATION OF PYRIDYL GRIGNARD REAGENTS AND CROSS COUPLING REACTIONS WITH SULFOXIDES BEARING AZAHETEROCYCLES
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Pyridyl Grignard reagents were prepared from the corresponding iodopyridine and EtMgBr.New cross coupling reactions of the Grignard reagents with azaheterocycles took place on the sulfinyl sulfur atom to afford biazaheteroaryls.
- Furukawa, Naomichi,Shibutani, Tadao,Fujihara, Hisashi
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p. 5845 - 5848
(2007/10/02)
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- Chemical Ionization Mass Spectrometry of Doxylamine and Related Compounds
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The chemical ionization mass spectrometric (CIMS) analysis of doxylamine, N,N-dimethyl-2-ethanamine, and related compounds, using both ammonia and methane as reagent gases, is discussed.The two reagent gases did not produce the same major fragment ion for doxylamine.Mechanisms for the fragmentation of doxylamine under either ammonia or methane CIMS conditions are proposed.The mechanisms explain the obsrevation of an m/z 182 fragment ion for doxylamine analyzed under methane CIMS conditions and an m/z 184 product ion detected under ammonia CIMS conditions.
- Korfmacher, Walter A.,Holder, Claude L.,Freeman, James P.,Mitchum, Ronald K.,Gosnell, Aubrey B.
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p. 435 - 439
(2007/10/02)
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- Applications of Organolithium and Related Reagents in Synthesis. Part 3. A General Study of the Reaction of Lithium Alkyls with Pyridine Ketones
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The reaction of MeLi and PhLi with acetylpyridines (1a-c) and their annelated derivatives (2a), (2b), (3), and (4) has been examined.The 3- and 4-pyridyl ketones (1b), (1c), (3), and (4) gave similar results to acetophenone and 3,4-dihydronaphthalen-1(2H)-one.In the case of the 2-pyridyl ketones (1a), (2a), and (2b) unexpectedly low yields of products resulted from the addition of RLi to the carbonyl group; the reaction was efficiently enhanced by initially adding an additional amount of LiBr.These results were accounted for by the chelation of RLi or LiBr by the 2-pyridyl ketones.
- Epsztajn, Jan,Bieniek, Adam
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p. 213 - 220
(2007/10/02)
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- Kinetic Energy Release and Position of Transition State during Intramolecular Aromatic Substitution in Ionized 1-Phenyl-1-(2-pyridyl)ethylenes
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The loss of substituents (X = H, CH3, Cl, Br, I) from the molecular ions of ortho-substituted 1-phenyl-1-(2-pyridyl)ethylenes 1a-f and of the isomeric 1-phenyl-1-(3-pyridyl)- and 1-phenyl-1-(4-pyridyl)ethylenes 2 and 3 has been investigated.Cyclic fragment ions a are formed from the ortho-substituted 1-phenyl-1-(2-pyridyl)ethylene molecular ions by an intramolecular aromatic substitution reaction.The energetic requirements of this reaction have been studied in dependence from the dissociation energy of the C-X bond by measurements of the ionization energies, appearance energies, and kinetic energies released during the reaction.The activation energy εh of the process varies only slightly with the dissociation energy of the C-X bond cleaved during the reaction, whereas the entalpy of reaction changes from positive (endothermic) to very negative (exothermic) values in the reaction series 1a-f.Consequently the reverse activation energy εr ranges from small to very large values in this series.This trend in εr is not followed by the kinetic-energy release.A large kinetic-energy release and energy partitioning quotient q = 0.7 - 1.0 is only observed for endothermic or thermoneutral processes, while a small kinetic-energy release and q ca. 0.2 is associated with exothermic reactions in spite of a large εr.This behavior has been correlated to the position Xo* of the transition state on the reaction coordinate according to Miller's quantification of the Hammond postulate.The release of εr as kinetic energy is only observed for reactions with "symmetrical" or "late" transition states (Xo* > 0.4) while most of εr remains as internal energy in the products of reactions with "early" transition states (Xo* 0.4).
- Schubert, Ralf,Gruetzmacher, Hans-Friedrich
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p. 5323 - 5328
(2007/10/02)
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