Regiospecific nucleophilic substitution in 2,3,4,5,6-pentafluorobiphenyl as model compound for supramolecular systems. Theoretical study of transition states and energy profiles, evidence for tetrahedral SN2 mechanism

2,3,4,5,6-Pentafluorobiphenyl (PFBi) was modified by the nucleophilic substitution of one fluorine using a series of O-, S- and N-nucleophiles, viz. alkaline salts of 2,2,2-trifluoro-ethanol, 3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctanol, 1,2;3,4-di-O-isopropylidenexylitol, allylsulfane, 3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctane-1-thiol, 3-aminopropan-1-ol (7), and tert-butyl N-(3-aminopropyl)carbamate (8). All the substitutions took place exclusively at the position para to the phenyl group. (3-Amino-propyl)amino derivative of PFBi (15) was further modified at the terminal amino group by acylation or fluoroalkylation. The reaction of 8 was applied to meso-5,10,15,20-tetrakis-(pentafluorophenyl)porphyrin (20) to afford tris- (21) and tetrakis-substituted (22) products with complete para-regioselectivity. Theoretical studies of the reaction pathways of PFBi with ammonia, microsolvated lithium fluoride or lithium hydroxide revealed that no Meisenheimer-type intermediates are formed in the course of the simulated reactions: instead, tetrahedral S_N2 mechanism was found. Significant regioselectivity of the nucleophilic aromatic substitution, leading to 4-substituted products, was predicted based on relative transition state energies in agreement with the observed experimental results.     

Fluorination of Organic Compounds with Cobalt Trifluoride and Elemental Fluorine in the Presence of Cobalt Trifluoride

Fluorination of organic compounds with cobalt trifluoride and elemental fluorine in the presence of cobalt trifluoride was studied. Fluorination with elemental fluorine proceeds under external-kinetic control at a constant rate. Examples of fluorination with elemental fluorine of certain fluorinated olefins and polyfluorinated paraffins in the presence of CoF₃ are presented.     

Synthesis and structure of N-(4-dialkylaminophenyl)hexafluoro-1,4-naphthoquinone 4-imines

The reaction of heptafluoro-1-naphthol with N,N-dialkyl-p-nitrosoanilines or N,N-dialkyl-p-phenylenediamines in the presence of HIO₃ gave the corresponding polyfluorinated N-aryl-1,4-naphthoquinone 4-imine derivatives which exist in solution as equilibrium mixtures of Z and E isomers. 2,3,5,6,7,8-Hexafluoro-N-(4-dimethylaminophenyl)-1,4-naphthoquinone 4-imine in crystal has exclusively the Z-isomer structure.     

Mechanisms of reactions of halogenated compounds: Part 7. Effects of fluorine and other groups as substituents on nucleophilic aromatic substitution

The effect of fluorine as a substituent group on nucleophilic aromatic substitution is discussed, where a fluorine atom located ortho to the point of substitution may be of variable activating influence, whereas fluorine located para is slightly deactivating and meta is activating. A rationale of these effects is presented and evidence to support polar influences by ortho fluorine is advanced. The influence of CN, CF₃, CF₂H and CFH₂ is also established by comparison of appropriate measured rate constants and compared with the activation effects of ring nitrogen.     

Double amination of 2-fluoroallylic acetates by palladium catalysts

We accomplished the palladium-catalyzed double substitution of 2-haloallylic acetates with nitrogen nucleophiles. During the Pd₂(dba)₃/DPPE-catalyzed reaction of 2-fluoroallylic acetates with N-substituted-p-toluenesulfonamide, two equivalents of nitrogen nucleophiles were introduced to the allyl unit with a Z-selectivity through the carbon–fluorine bond cleavage. We further demonstrated the reaction of 2-chloroallylic acetates, and succeeded in obtaining the same doubly-substituted products in good yields with a high Z-selectivity.     

Synthesis of halo-fluoro-substituted adamantanes by electrophilic transannular cyclization of bicyclo[3.3.1]nonane dienes

3,7-Dimethylenebicyclo[3.3.1]nonane and its derivatives with a methyl or phenyl substituent in a methylene group react, with N-halosuccinimides NXS (X=Cl, Br, I) in dichloromethane in the presence of tetrabutylammonium dihydrotrifluoride or polyfluorinated alcohols via a transannular cyclization leading to the corresponding 1-fluoro- or 1-polyfluoroalkoxy-3-halomethyladamantanes. The reaction of the dienes with NXS and Bu₄N⁺H₂F₃⁻ conducted in THF, oxetane or ethylene oxide runs through a cascade addition of electrophiles (positively charged halogen atoms) and external nucleophiles (solvent molecules and halide anions) to the starting diene substrate and intermediate adamantyl carbocation.     

1-Fluorosilatrane synthesis from SiF4 complexes and its properties

A new method of 1-fluorosilatrane synthesis on the basis of silicon tetrafluoride complexes obtained from SiO₂ is offered. Chemical properties of 1-fluorosilatrane in reactions of nucleophilic substitution are investigated. It is shown that fluorine can be substituted by O-nucleophiles (lithium methoxide, isopropoxide and phenoxide) and C-nucleophile (lithium phenylacetylenide).     

17O-NMR study of polyfluorinated alcohols and ethers

δ¹⁷O values are reported for 16 polyfluorinated alcohols and ethers. The ¹⁷O-nuclear shielding increases with fluorine substituents in γ-position and it decreases (much more than expected by comparison with δ¹³C-values) with fluorine substituents in β- position. The π-interactions between oxygen and a vinyl or a phenyl group (α,β -unsaturation) are greatly reduced if a CHF₂CF₂ group is attached to the oxygen. Conclusions from δ¹⁷O- data are supported by ¹³C-, ¹¹B- and ²⁹Si-chemical shifts.     

Stereoselective conjugate addition reactions of lithium amides to α,β-unsaturated chiral iron acyl complexes [(η-C5H5)Fe(CO)(PPh3)(COCHCHR)]

Conjugate addition of achiral lithium dimethylamide to the chiral iron cinnamoyl complexes (S,E)- and (S,Z)-[(η⁵-C₅H₅)Fe(CO)(PPh₃)(COCHCHPh)] proceeds with high diastereoselectivity, with this protocol being used to establish unambiguously the absolute configuration of Winterstein’s acid (3-N,N-dimethylamino-3-phenylpropanoic acid) as (R). The highly diastereoselective conjugate addition of lithium N-benzyl-N-trimethylsilylamide to a range of α,β-unsaturated iron acyl complexes, followed by in-situ elaboration of the derived enolate by either alkylation or aldol reactions is also demonstrated, facilitating the stereoselective synthesis of both cis- and trans-β-lactams. This methodology has been used to effect the formal asymmetric syntheses of (±)-olivanic acid and (±)-thienamycin. Addition of chiral lithium amides derived from primary and secondary amines to the iron crotonyl complex [(η⁵-C₅H₅)Fe(CO)(PPh₃)(COCHCHMe)] indicates that lithium N-α-methylbenzylamide shows low levels of enantiorecognition, while lithium N-3,4-dimethoxybenzyl-N-α-methylbenzylamide and lithium N-benzyl-N-α-methylbenzylamide show high levels of enantiodiscrimination. The high level of observed enantiorecognition was used to facilitate a kinetic resolution of (RS)-[(η⁵-C₅H₅)Fe(CO)(PPh₃)(COCHCHMe)] with homochiral lithium (R)-N-3,4-dimethoxybenzyl-N-α-methylbenzylamide. Further mechanistic studies show that conjugate additions of (RS)-lithium N-benzyl-N-α-methylbenzylamide to either the (RS)- or homochiral iron crotonyl complex show 2:1 stoicheiometry, while homochiral lithium N-benzyl-N-α-methylbenzylamide shows 1:1 stoicheiometry.     

Solution phase structures of enantiopure and racemic lithium N-benzyl-N-(α-methylbenzyl)amide in THF: low temperature 6Li and 15N NMR spectroscopic studies

The antipodes of lithium N-benzyl-N-(α-methylbenzyl)amide are highly efficient enantiopure ammonia equivalents for the asymmetric synthesis of β-amino acid derivatives via conjugate addition to α,β-unsaturated esters. ⁶Li and ¹⁵N NMR spectroscopic studies of doubly labelled ⁶lithium (S)-¹⁵N-benzyl-¹⁵N-(α-methylbenzyl)amide in THF at low temperature reveal the presence of lithium amide dimers as the only observable species. Either a monomeric or dimeric lithium amide reactive species can be accommodated within the transition state mnemonic for this class of conjugate addition reaction. This enantiopure lithium amide offers unique opportunities over achiral (e.g., lithium dibenzylamide) and C₂-symmetric (e.g., lithium bis-N,N-α-methylbenzylamide) counterparts for further mechanistic study owing to the ready distinction of the various dimers formed.     

Polyfunctional molecules in processes of aromatic nucleophilic substitution 3. Pentaf luoropyridines as scaffolds for synthesis of liquid-phase combinatorial libraries based on S N Ar processes

A possibility of using polyfluorinated pyridines as multiply modified molecules, i.e., scaffolds, in processes of aromatic nucleophilic substitution (S _N Ar) for the synthesis of liquid-phase combinatorial libraries was studied. The real and “virtual” combinatorial libraries of diaryl ethers were synthesized by the reactions of pentafluoropyridine with phenol and its derivatives. Some criteria for the estimation of the quality of the libraries were formulated. A rational methodology for the preparation of representative combinatorial mixtures on the basis of processes of the S _N Ar type in polyfluorinated arenes was proposed. The libraries can be used in highly efficient biological screening of low-molecular-weight regulators of transferase functioning. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 5, pp. 945–950, May, 2007.     

Unusual β,β′-coupling and β-alkylation of methyl 2,3,3-trifluoropropenoate by lithium diorganocuprates

Methyl 2,3,3-trifluoroprop-2-enoate (1) reacts with lithium diorganocuprates in two ways, by fluorine substitution at C-3 with alkyl or aryl, or by β,β′ C,C-coupling. The reaction product was strongly dependent on the organyl structure: while dibutyl- or diphenylcuprate reacted by C-3 substitution, dimethylcuprate afforded the product of the coupling, dimethyl (Z,Z)-2,3,4,5-tetrafluorohexa-2,4-dienedioate (3). (Z)-Configuration is highly prevailing in 3-alkylated 2,3-difluoropropenoates (77-90% rel.).     

Intramolecular oxidative addition of C-F and C-H bonds to [Pt(dba)2]. Crystal structure of [PtCl{Me2NCH2CH2NCH(2,4,5-C6HF3)}]

The reactions of compound [Pt(dba)₂] with ligands RCHNCH₂CH₂NMe₂ (1a-1f) in which R is a fluorinated aryl ring produced activation of C-F bonds when two fluorine atoms are present in the ortho positions of the aryl ring or activation of C-H bonds for ligands containing only one fluoro substituent in ortho. Both C-F and C-H bond activation are favoured by an increase of the degree of fluorination of the ring. Further reaction with lithium halides produced cyclometallated platinum (II) compounds [PtX(Me₂NCH₂CH₂NCHR)] (X = Br, Cl) (2) containing a terdentate [C,N,N′] ligand. The obtained compounds were fully characterized including a structure determination for [PtCl{Me₂NCH₂CH₂NCH(2,4,5-C₆HF₃)}] (2d′).     

Urea and thiourea complexes with trifluoromethanesulfonic acid and its derivatives

Urea and thiourea form complexes with trifluoromethanesulfonic acid, its monohydrate, and lithium salt CF₃SO₃Li. Urea complexes with trifluoromethanesulfonic acid are also formed as a result of hydrolysis in the reaction of N,N′-bis(trimethylsilyl)carbodiimide or cyanamide with trifluoromethanesulfonic acid in water.     

Lithium-bis(silyl)amide und Tris(silyl)amine Synthese und Kristallstrukturen

Lithium Bis(silyl)amides and Tris(silyl)amines Synthesis and Crystal Structures Lithiated di-tert-butylfluorosilylamine reacts with difluorosilanes by substitution ( 1, 2 ). The siloxy-( 3, 4 ) and tert-butyloxy-( 5 )-silylamines are formed in reaction of 1 and 2 with LiOR (R = SiMe₃, CMe₃). The lithium derivatives of 3 and 4 are dimers forming an (LiFSiN)₂-eight-membered ring ( 6, 7a ). Using 12 crown-4 the amide and the coordinated lithium are forming free ions ( 7 c ). The lithium derivative of 5 ( 8 ) crystallizes as a dimeric LiF-adduct of an iminosilane, forming a LiF-four-membered ring. In thf 7 reacts with Me₃SiCl by a fluorine/chlorine exchange and 9 is obtained. In 9 lithium is coordinated with nitrogen, oxygen and two thf molecules, forming an (SiNOLi)-four-membered ring. 6 and 7 react with fluorosilanes to give tris(silyl)amines 10 – 12 .     

Theoretical study on activation mechanism of fluorine substitution reactions of Keggin-MAl12 in aqueous solutions

The fluorine substitution reactions of Keggin polymeric aluminum species K-MAl₁₂ (M = Al, Ga, Ge) were investigated using density functional theory. Two substitution pathways (associative and dissociative) were simulated. The results show that the replacement of charged tetrahedral center metals causes the change in energy barrier either for associative mechanism or dissociative mechanism. The preferred activation mechanisms are proposed by comparing associative and dissociative barriers for fluorine substitution reactions of three Keggin Al species. The fluorine substitution reactions of Al₁₃ and GaAl₁₂ are inclined to dissociative mechanism and GeAl₁₂ follows an associative mode, indicating a mechanistic variation induced by the alteration of tetrahedral metals.     

Reactions of polyfluorinated 2,5-cyclohexadienones at the carbonyl group

Perfluoro-4-phenoxy-2,5-cyclohexadienone reacts with phenyl- and pentanuorophenylhydrazines to give products of nucleophilic substitution of the fluorine atom at the double bond, 3-arylazotetrafluorophenols. In the presence of aluminum chloride, the reactions proceed at the carbonyl groups of polyfluorinated cyclohexadienones to form the corre sponding polyfluorinated azobenzenes. Perfluoro-4-phenoxy-2,5-cyclohexadierione reacts with butyllithium and butylmagnesium bromides to give the product of addition at the carbonyl group.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 7, pp. 1778–1781, July, 1996.     

2-(Fluorophenyl)pyridines by the Suzuki-Miyaura method: Ag2O accelerates coupling over undesired ipso substitution (SNAr) of fluorine

Problematic ipso substitution was observed in the Suzuki-Miyaura coupling of pentafluorophenylboronic acid to make 2-pentafluorophenylpyridine. Strong bases favored coupling, but under these conditions fluorine in the product tended to undergo nucleophilic substitution. Inclusion of Ag₂O accelerated coupling over ipso substitution.     

Nucleophilic aromatic substitution; kinetics of fluorine-18 substitution reactions in polyfluorobenzenes. Isotopic exchange between 18F− and polyfluorobenzenes in dimethylsulfoxide. A kinetic study

Nucleophilic aromatic substitution reactions of C₆F₆, C₆XF₅ (XH, Cl, Br), C₆H₂F₄, oC₆H₄FNO₂ and pC₆H₄FNO₂ by the fluoride anion were studied in DMSO utilizing fluorine-18. Substitution of fluorine by fluorine-18 is the only reaction observed with a C₆F₆ substrate. With other substrates fluorine substitution is predominant. The kinetic studies provide results consistent with a S_NAr two step mechanism and suggest an intermediate analogous to that for electrophilic aromatic substitution. Consideration of σ^? indicates consistency with methoxide ion substitution results with similar substrates. The possible utility of these reactions in labeling aromatic compounds is noted.     

Synthesis and applications of the first polyfluorous proline derivative

Starting from trans-4-hydroxy-l-proline, a polyfluorinated proline derivative having a fluorine content of 54% has been prepared. It has been tested as a catalyst in the aldol reaction between p-nitrobenzaldehyde and acetone with 73% ee in BTF and in copper(I)-catalyzed allylic oxidation of cyclohexene with 20% ee in HFIP.