A Theoretical Study of the Relationship between Secondary .alpha.-Deuterium Kinetic Isotope Effects and the Structure of SN2 Transition States

Poirier, Raymond A.; Wang, Youliang; Westaway, Kenneth Charles

doi:10.1021/ja00085a037

Cited by 131 publications

(104 citation statements)

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“…5). The frequencies of bending modes have been shown to contribute significantly to the normal secondary isotope effect observed for S N 2 reactions in alkyl and ethyl halides (17)(18)(19)(20). In our computational model, the O-H stretch and OH ip bend are clean modes that are easily mapped in the H/D-substituted reactant and TS complexes.…”

Section: Resultsmentioning

confidence: 85%

Further insights into the mechanism of the reaction of activated bleomycin with DNA

Chow

Liu

Solomon

2008

Proc. Natl. Acad. Sci. U.S.A.

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Bleomycin (BLM) is a glycopeptide anticancer drug that effectively carries out single-and double-stranded DNA cleavage. Activated BLM (ABLM), a low-spin ferric-hydroperoxide, BLM-Fe III -OOH, is the last intermediate detected before DNA cleavage. We have previously shown through experiments and DFT calculations that both ABLM decay and reaction with H atom donors proceed via direct H atom abstraction. However, the rate of ABLM decay had been previously found, based on indirect methods, to be independent of the presence of DNA. In this study, we use a circular dichroism (CD) feature unique to ABLM to directly monitor the kinetics of ABLM reaction with a DNA oligonucleotide. Our results show that the ABLM ؉ DNA reaction is appreciably faster, has a different kinetic isotope effect, and has a lower Arrhenius activation energy than does ABLM decay. In the ABLM reaction with DNA, the small normal k H/kD ratio is attributed to a secondary solvent effect through DFT vibrational analysis of reactant and transition state (TS) frequencies, and the lower E a is attributed to the weaker bond involved in the abstraction reaction (C-H for DNA and N-H for the decay in the absence of DNA). The DNA dependence of the ABLM reaction indicates that DNA is involved in the TS for ABLM decay and thus reacts directly with BLM-Fe III -OOH instead of its decay product.non-heme iron ͉ kinetics ͉ isotope effects ͉ reactivity B leomycins (BLMs) (Fig. 1) are a group of glycopeptide antibiotics that are used clinically to treat Hodgkin's lymphoma, head and neck tumors, and testicular cancer (1-4). Activated BLM (ABLM), a low-spin ferric hydroperoxide complex, BLM-Fe III -OOH, (5-7) is the last intermediate detected before DNA strand cleavage (8, 9). ABLM can be formed from the reaction of Fe II BLM with O 2 and one additional electron (8, 10). Through deuterium and tritium labeling studies, it was established that DNA cleavage involves H atom abstraction from the C4Ј of the deoxyribose sugar (11,12). O 18 isotope studies indicated that O-O bond cleavage is in the rate-determining step (13). We have recently provided strong experimental and computational evidence that ABLM decay and reactions with H atom donors proceed via H atom abstraction by the low-spin ferric hydroperoxide (14). However, an alternative mechanism that parallels heme chemistry was recently reemphasized, where BLM-Fe III -OOH is protonated and decays to produce the H atom abstracting species, BLM-Fe V AO, via heterolytic cleavage of the O-O bond (15). This heterolytic cleavage mechanism would not show a dependence on H atom availability and would appear to be ruled out by the fact that the decay of ABLM is accelerated by H atom donors. However, the rate of ABLM reaction with DNA as the substrate had been experimentally observed to be very similar to that in the absence of DNA (8). In those experiments, the rate of the ABLM reaction was studied by using primarily the indirect method of quantitative analysis of DNA product. We have defined a method to directly monitor the decay...

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Section: Resultsmentioning

confidence: 85%

Further insights into the mechanism of the reaction of activated bleomycin with DNA

Chow

Liu

Solomon

2008

Proc. Natl. Acad. Sci. U.S.A.

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“…The study of KIEs in such reactions is of particular interest. There have been numerous experimental [1][2][3][4][5][6][7][8][9][10][11][12][13][14]22,23 and theoretical [15][16][17][18][19][20][21][24][25][26][27][28][29][30][31][32][33][34] studies performed on proton transfer in systems of chemical and biochemical interest.…”

Section: Introductionmentioning

confidence: 99%

Primary and Solvent Kinetic Isotope Effects in the Water-Assisted Tautomerization of Formamidine: An ab Initio Direct Dynamics Study

Bell

Truong

1997

J. Phys. Chem. A

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We present an ab initio direct dynamics study of the primary and solvent kinetic isotopes effects (KIEs) for the water-assisted tautomerization in the formamidine-water complex. These calculations are based on a variational transition state theory plus multidimensional semiclassical tunneling corrections with potential energy information calculated at the MP2 level of theory using the 6-31G(d,p) basis set. We found that both the primary and solvent KIEs are large at low temperatures and are due not only to tunneling but also to quantum effects in vibrational motions. The primary KIEs were larger than the solvent KIEs. This results from differences due to the effect of deuteration on vibrational modes. Bending modes show significant inverse KIEs, while those of the reactive OH and NH vibrations show both inverse and normal effects. Such effects can be explained by examining changes in the zero-point energies of these modes. The adherence of the HH/HD/DD rates to the rule of the geometric mean is also examined.

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“…[21][22][23][24][25][26][27] In contrast, the DKIEs can only be secondary inverse (k H /k D < 1.0) in a stepwise process (or a normal S N 2 reaction) because the N-H(D) vibrational frequencies invariably increase upon going to the TS because of an increase in the steric congestion. [28][29][30] In this respect, DKIEs have provided a useful means to determine the TS structures in the nucleophilic substitution reactions, as well as how the reactants alter the TS structures, particularly through changes in the substituents. The incorporation of deuterium in the nucleophile has an advantage in that the α-DKIEs reflect only the degree of bond formation, particularly for the secondary inverse DKIEs.…”

Section: -7mentioning

confidence: 99%

Kinetics and Mechanism of the Anilinolysis of Aryl Ethyl Isothiocyanophosphates in Acetonitrile

Barai¹,

Adhikary²,

Lee³

2013

Bulletin of the Korean Chemical Society

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The nucleophilic substitution reactions of Y-aryl ethyl isothiocyanophosphates with substituted X-anilines and deuterated X-anilines were investigated kinetically in acetonitrile at 75.0 o C. The free energy relationships with X in the nucleophiles exhibited biphasic concave downwards with a break point at X = H. A stepwise mechanism with rate-limiting bond formation for strongly basic anilines and with rate-limiting bond breaking for weakly basic anilines is proposed based on the negative and positive ρ XY values, respectively. The deuterium kinetic isotope effects (DKIEs; k H /k D ) changed gradually from primary normal with strongly basic anilines, via primary normal and secondary inverse with aniline, to secondary inverse with weakly basic anilines. The primary normal and secondary inverse DKIEs were rationalized by frontside attack involving hydrogen bonded, four-center-type TSf and backside attack involving in-line-type TSb, respectively.

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A Theoretical Study of the Relationship between Secondary .alpha.-Deuterium Kinetic Isotope Effects and the Structure of SN2 Transition States

Cited by 131 publications

References 0 publications

Further insights into the mechanism of the reaction of activated bleomycin with DNA

Further insights into the mechanism of the reaction of activated bleomycin with DNA

Primary and Solvent Kinetic Isotope Effects in the Water-Assisted Tautomerization of Formamidine: An ab Initio Direct Dynamics Study

Kinetics and Mechanism of the Anilinolysis of Aryl Ethyl Isothiocyanophosphates in Acetonitrile

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