1997 Alfred Bader Award Lecture Reactivities of arylnitrenium ions with guanine derivatives and other nucleophiles

1998 ◽  
Vol 76 (10) ◽  
pp. 1327-1337 ◽  
Author(s):  
Robert A McClelland ◽  
Timothy A Gadosy ◽  
Daniel Ren
Keyword(s):  
Rate Constants ◽  
Flash Photolysis ◽  
Lone Pair ◽  
Primary Amines ◽  
Diffusion Limit ◽  
Nitrenium Ions ◽  
Carbenium Ions ◽  
Alkyl Amines ◽  
Guanine Derivatives ◽  
Arylnitrenium Ions

The carcinogens 4-aminobiphenyl and 2-aminofluorene are metabolized to hydroxylamine esters that undergo N-O heterolysis to produce arylnitrenium ions that react with DNA, especially at guanine residues. These nitrenium ions and a number of their derivatives have been studied by the laser flash photolysis technique, to provide direct kinetic information about the lifetimes of the electrophiles in water and their reactivities with added nucleophiles. Arylnitrenium ions ArNH+ are longer-lived in water than arylcarbenium analogs ArCH2+, in some cases significantly longer-lived. The nitrenium ions do react with azide ion at the diffusion limit (providing the cation is not highly stabilized). This behaviour completely parallels that of carbenium ions. The biphenylyl- and fluorenylnitrenium ions react with guanine derivatives such as 2-deoxyguanosine (dG) with rate constants that are close to or at the diffusion limit (2 × 109 M-1 s-1) for the more reactive cations. Thus, in spite of cation lifetimes of the order of 100 ns to a millisecond in water, dG effectively competes with the solvent. The product is a C8 adduct, the same adduct observed with carcinogenic arylamines and DNA. With delocalized carbenium ions that have similar lifetimes, guanine derivatives compete very poorly with water. Thus, arylnitrenium ions have high dG:water selectivities; arylcarbenium ions have low selectivities. Nitrenium ions and carbenium ions do have parallel reactivities with primary alkyl amines. More reactive cations show a greater reactivity with less basic amines and the rate constants level below the diffusion limit. This can be explained by hydrogen bonding of the amine lone pair. Using the NH2 group of the alkyl amines as a model for the C2-NH2 group of guanine shows why nitrenium ions show no detectable reactivity at this site. The rate constant for the nitrenium-guanine reaction that forms the C8 adduct is at least an order of magnitude greater than that of a nitrenium-NH2 reaction. Nitrenium ions do form a guanine-NH2 adduct in DNA, suggesting that incorporation into the polymer changes reactivity patterns. With imidazoles, nitrenium ions show reactivity trends that parallel the nitrenium-dG reaction, with rate constants levelling at the 2 × 109 limit for the more reactive cations. Imidazole itself and 1-methylimidazole are generally less reactive than dG, while 2-methylimidazole and 1,2-dimethylimidazole are very similar. A Brönsted-like plot incorporating points for dG, primary amines and imidazoles shows no correlation of nitrenium rate constants with nitrogen basicity. This is true even if only dG and imidazoles are considered. Thus a previous correlation of nitrenium reactivity with purine N7 basicity is suspect. The conclusion is that there is some feature of guanine that makes its reaction with nitrenium ions unusually fast. The reasons for this are not immediately apparent, especially since there is conflicting evidence as to the detailed nature of the mechanism of the reaction that forms the C8 adduct. Key words: nitrenium, aryl azide, guanine, DNA, carcinogen.

Carbocation-like reactivity patterns in X'-substituted-4-biphenylylnitrenium ions

1998 ◽  
Vol 76 (1) ◽  
pp. 78-84 ◽  
Author(s):  
Daniel Ren ◽  
Robert A McClelland
Keyword(s):  
Positive Charge ◽  
Flash Photolysis ◽  
Substituent Effects ◽  
Diffusion Limit ◽  
Poor Correlation ◽  
Carbenium Ions ◽  
Azide Ion ◽  
Arylnitrenium Ions ◽  
Reaction With Water ◽  
Two Parameter

4-Azido-X'-substituted biphenyls (X' = 4'-MeO, 4'-Me, 4'-F, 3'-Me, 4'-Cl, H, 3'-MeO, 3'-Cl, 4'-CF3) have been prepared and subjected to 248 nm flash photolysis irradiation in 20:80 acetonitrile:water. Transient X'-substituted 4-biphenylylnitrenium ions 10 (Ar C6H4-N + H) are observed, with lifetimes ranging from 0.6 ms (4'-MeO) to 26 ns (4'-CF3). These cations are quenched by azide ion, with values of kaz ranging from 6 to 10 x 109 M-1 s-1, with the majority in the range (9-10) x 109. This near constant kaz provides further evidence that arylnitrenium ions are quenched by azide ion at the diffusion limit. The solvent reactivities, plotted in a single-parameter Hammett plot against σ sup + (X), exhibit a poor correlation, with the points for the para π-electron donors deviating from the correlation line based on the other substituents in the direction of requiring a more negative substituent parameter. The data are more satisfactorily fit to the two-parameter Yukawa-Tsuno equation; the parameter r + obtained in this fit is 2.8. Thus the resonance interaction of the para π -donor X'-substituents with the positive charge of the cation is underestimated by σ sup + , a situation that has previously been observed with benzylic-type carbenium ions. The conclusion is made that, in their reaction with water, 4-biphenylylnitrenium ions behave like benzyl cations bearing two additional stabilizing vinyl groups, i.e., as if they had the structure Ar-C + (C = C)2. The inherent reactivity and the pattern of the aryl substituent effects are in fact similar to those in the carbocation series Ar-C + (Ph)2.Key words: nitrenium, nitrene, aryl azide, photochemistry, lifetime.

Reaction of arylnitrenium ions with guanine derivatives: N1-methylguanosine and N2,N2-dimethylguanosine

2001 ◽  
Vol 79 (12) ◽  
pp. 1881-1886 ◽  
Author(s):  
Bernice Cheng ◽  
Robert A McClelland
Keyword(s):  
Rate Constants ◽  
Flash Photolysis ◽  
Initial Step ◽  
Direct Reaction ◽  
Ph Profile ◽  
Nitrenium Ion ◽  
Base Form ◽  
Guanine Derivatives ◽  
Arylnitrenium Ions ◽  
Conjugate Base

A prior flash photolysis study of the direct reaction of arylnitrenium ions with 2'-deoxyguanosine identified a second intermediate that grew in as the transient nitrenium ion reacted with the nucleoside. This intermediate was identified as the the product of the addition of the nitrenium ion to the C-8 position of guanine prior to loss of the C-8 proton — the C-8 intermediate. A feature of the C-8 intermediate is that it exists in acid–base forms. This behavior was evident in both a spectroscopic analysis as well as in the rate–pH profile, which showed a break around pH 4 from a pH-independent reaction to a reaction that was first-order in H+. The present study was designed to identify the structure of the conjugate base form. This involved a kinetic study of the decay of the C-8 intermediate derived from the reaction of the 2-fluorenylnitrenium ion with N1-methylguanosine and N2,N2-dimethylguanosine. The rationale was that the former is unable to lose the N-1 proton, while the latter cannot deprotonate at the NH2 group. The rate–pH profiles clearly show that it is the N-1 proton that is acidic. The rate constants for the C-8 intermediate of N2,N2-dimethylguanosine show the same downward break observed with 2'-deoxyguanosine and guanosine associated with conversion to the conjugate base form. In contrast, the rate constants for the N1-methylguanosine intermediate are independent of pH. Rate constants for the reaction forming the C-8 intermediate are also reported. These show that the reaction of nitrenium ions with the N2,N2-dimethylguanine derivative is significantly faster (except where the reactions are diffusion controlled). This is consistent with the initial step of the reaction of an arylnitrenium ion and guanine occurring by direct addition at C-8. The developing positive charge in such a reaction can be delocalized to the C-2 position where π donors such as NH2 and NMe2 can exert a stabilizing effect.Key words: nitrenium, arylnitrenium, guanosine, DNA adduct.

Structures of Reactive Nitrenium Ions:  Time-Resolved Infrared Laser Flash Photolysis and Computational Studies of SubstitutedN-Methyl-N-arylnitrenium Ions

2000 ◽  
Vol 122 (34) ◽  
pp. 8271-8278 ◽  
Author(s):  
Sanjay Srivastava ◽  
Patrick H. Ruane ◽  
John P. Toscano ◽  
Michael B. Sullivan ◽  
Christopher J. Cramer ◽  
...  
Keyword(s):  
Flash Photolysis ◽  
Laser Flash Photolysis ◽  
Laser Flash ◽  
Infrared Laser ◽  
Computational Studies ◽  
Time Resolved ◽  
Nitrenium Ions ◽  
Arylnitrenium Ions

α-Ketophosphonates in the Synthesis of α-iminophosphonates

2020 ◽  
Vol 7 (2) ◽  
pp. 226-238
Author(s):  
Petro P. Ony`sko ◽  
Tetyana I. Chudakova ◽  
Vladimir V. Pirozhenko ◽  
Alexandr B. Rozhenko
Keyword(s):  
Bond Cleavage ◽  
Direct Synthesis ◽  
Equilibrium Mixture ◽  
Primary Amines ◽  
Alkyl Amines ◽  
Protic Solvents ◽  
Metallic Salts ◽  
Direct Preparation ◽  
Stage Synthesis ◽  
Aprotic Dipolar Solvent

The potentialities of condensation of α-ketophosphonates with primary amines for direct synthesis of α-iminophosphonates have been revealed. Diesters of α-ketophosphonic acids react with the primary amines by two competitive pathways: with a formation of α-iminophosphonates or a C-P bond cleavage resulting in a hydrogen phosphonate and an acylated amine. In many cases, the latter undesirable pathway is dominant, especially for more nucleophilic alkyl amines. Using metallic salts of α-ketophosphonates avoids the C-P bond cleavage, allowing direct preparation of α-phosphorylated imines by the reaction with primary amines. This strategy provides an atom economy single-stage synthesis of iminophosphonates – precursors of bio relevant phosphorus analogs of α-amino acids. Methyl sodium iminophosphonates, bearing aryl or heteryl substituents at the imino carbon atom exist in solutions at room temperature as an equilibrium mixture of Z- and E-isomers. A configuration of the C=N bond can be controlled by the solvent: changing the aprotic dipolar solvent DMSO-d6 by water or alcohols leads to the change from a predominant Z-isomer to almost an exclusive E-form. In contrast, diesters of the respective iminophosphonates exist in non-protic solvents predominantly in Econfiguration. The solvent effect on E-Z stereochemistry is demonstrated by DFT calculations.

Singlet Methylene Removal Rate Constants from the (0,1,0) Vibrational Level: Enhancement via Complex-Mediated Vibrational Relaxation

2001 ◽  
Vol 215 (6) ◽  
Author(s):  
M.A. Buntine ◽  
G.J. Gutsche ◽  
W.S. Staker ◽  
M.W. Heaven ◽  
K.D. King ◽  
...  
Keyword(s):  
Vibrational Level ◽  
Rate Constants ◽  
Vibrational Relaxation ◽  
Flash Photolysis ◽  
Laser Flash Photolysis ◽  
Removal Rate ◽  
Laser Flash ◽  
Laser Absorption ◽  
Photolysis Laser ◽  
Singlet Methylene

The technique of laser flash photolysis/laser absorption has been used to obtain absolute removal rate constants for singlet methylene,

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