Secondary kinetic deuterium isotope effects on unimolecular cleavage reactions: Zero-point vibrational energy and qualitative RRKM theory.

Secondary kinetic isotope effects arise as the result of transition-state zero-point vibrational energy differences. Unimolecular simple cleavage reactions of gas-phase ions in mass spectrometers allow detailed studies of isotope effects on competing reactions, particularly when examined in intramolecular competition experiments where interpretation requires very few simplifying assumptions. The zero-point energy differences reflect changes of isotope sensitive vibrational properties, and both α- and ß-secondary deuterium isotope effects are related to the sp 3 → sp 2 hybridization changes that accompany bond cleavage. Deuterium substitution three bonds or more removed from the bond broken also gives rise to isotope effects, but their origin is less easily interpreted. The magnitude and variation of the observed effects depend not only on zero-point energy differences; a number of additional factors play a role. The influence of the critical energy, the excess energy, the size of the reactant, and the presence of competing reactions can be rationalized within a simple, qualitative RRKM framework. The distinction between kinetic and thermodynamic isotope effects is not always obvious.

Possible Intermediacy of Cyclopropane Complexes in the Isomerization of Aliphatic Amine Radical Cations.

The isomerization of aliphatic amine radical cations via intermediate [cyclopropane-NH3]+• and [cyclopropane-amine]+• ion-neutral complexes was studied experimentally with double-focusing mass spectrometers and computationally with composite ab initio methods. The results examine and extend Audier's suggestion that primary amine radical cations with alkyl substituents at the ß- and/or γ-carbon atoms isomerize via transient complexes of NH3 and alkyl cyclopropanes; these are formed by ring closure of the easily accessible γ-distonic isomers. Ionized amines with substituents at the α-carbon may react analogously when trialkyl cyclopropane complexes can be formed. Isomerization via complex intermediates is a major reaction pathway when the internal energy of the amine radical cation is less than that required for simple CC-bond cleavage. Complexes of unsubstituted or monosubstituted ionized cyclopropanes rarely contribute to the isomerization reactions. Secondary and tertiary amine radical cations do not undergo isomerization via cyclopropane intermediates, whereas aliphatic ether radical cations do.

Isomerization of metastable amine radical cations by dissociation-recombination.

The metastable molecular ions of primary aliphatic amines branched at C2 can isomerize by cleavage-recombination, thereby facilitating fragmentation reactions that require less energy than simple cleavage of the initial molecular ion. This process complements the reactions described by Audier to account for the conspicuous absence of the conventional a-cleavage among the major fragmentation reactions of the metastable molecular ions of primary amines.

The α-effect in gas-phase SN2 reactions of microsolvated anions: methanol as a solvent.

The α-effect, an enhanced reactivity of nucleophiles with a lone-pair adjacent to the reaction center, has been studied in solution for several decades. The gas-phase α-effect has recently been documented in studies of SN2 reactions as well as in competing reactions for both bare and microhydrated anions. In the present work we extend our studies of the significance of microsolvation on the α-effect, employing methanol as the solvent, in the expectation that the greater stability of the methanol cluster relative to the water cluster will lower the reactivity and thereby allow studies over a wider efficiency range. We compare the gas-phase reactivity of the microsolvated α-nucleophile HOO(-)(CH3OH) to that of microsolvated normal alkoxy nucleophiles, RO(-)(CH3OH) in reactions with CH3Cl and CH3Br. The results reveal enhanced reactivity of HOO(-)(CH3OH) toward both methyl halides relative to the normal nucleophiles, and clearly demonstrate the presence of an α-effect for the microsolvated α-nucleophile. The highly exothermic reactions with methyl bromide result in a smaller Brønsted ßnuc value than observed for methyl chloride, and the α-effect in turn influences the reactions with methyl chloride more than with methyl bromide. Computational investigations reveal that reactions with methyl bromide proceed through earlier transition states with less advanced bond formation compared to the related reactions of methyl chloride. In addition, solvent interactions for HOO(-) are quite different from those with the normal nucleophiles at the transition state, indicating that differential solvation may well contribute to the α-effect. The greater thermodynamic and kinetic stability of the anion-methanol clusters relative to the anion-water clusters accounts well for the differences in the influence of solvation with the two protic polar solvents.

The α-effect and competing mechanisms: the gas-phase reactions of microsolvated anions with methyl formate.

The enhanced reactivity of α-nucleophiles, which contain an electron lone pair adjacent to the reactive site, has been demonstrated in solution and in the gas phase and, recently, for the gas-phase S(N)2 reactions of the microsolvated HOO(-)(H2O) ion with methyl chloride. In the present work, we continue to explore the significance of microsolvation on the α-effect as we compare the gas-phase reactivity of the microsolvated α-nucleophile HOO(-)(H2O) with that of microsolvated normal alkoxy nucleophiles, RO(-)(H2O), in reactions with methyl formate, where three competing reactions are possible. The results reveal enhanced reactivity of HOO(-)(H2O) towards methyl formate, and clearly demonstrate the presence of an overall α-effect for the reactions of the microsolvated α-nucleophile. The association of the nucleophiles with a single water molecule significantly lowers the degree of proton abstraction and increases the S(N)2 and B(AC)2 reactivity compared with the unsolvated analogs. HOO(-)(H2O) reacts with methyl formate exclusively via the B(AC)2 channel. While microsolvation lowers the overall reaction efficiency, it enhances the B(AC)2 reaction efficiency for all anions compared with the unsolvated analogs. This may be explained by participation of the solvent water molecule in the B(AC)2 reaction in a way that continuously stabilizes the negative charge throughout the reaction.

Investigating the α-effect in gas-phase S(N)2 reactions of microsolvated anions.

The α-effect-enhanced reactivity of nucleophiles with a lone-pair adjacent to the attacking center-was recently demonstrated for gas-phase S(N)2 reactions of HOO(-), supporting an intrinsic component of the α-effect. In the present work we explore the gas-phase reactivity of microsolvated nucleophiles in order to investigate in detail how the α-effect is influenced by solvent. We compare the gas-phase reactivity of the microsolvated α-nucleophile HOO(-)(H2O) to that of microsolvated normal alkoxy nucleophiles, RO(-)(H2O), in reaction with CH3Cl using a flowing afterglow-selected ion flow tube instrument. The results reveal enhanced reactivity of HOO(-)(H2O) and clearly demonstrate the presence of an α-effect for the microsolvated α-nucleophile. The association of the nucleophile with a single water molecule results in a larger Brønsted ßnuc value than is the case for the unsolvated nucleophiles. Accordingly, the reactions of the microsolvated nucleophiles proceed through later transition states in which bond formation has progressed further. Calculations show a significant difference in solvent interaction for HOO(-) relative to the normal nucleophiles at the transition states, indicating that differential solvation may well contribute to the α-effect. The reactions of the microsolvated anions with CH3Cl can lead to formation of either the bare Cl(-) anion or the Cl(-)(H2O) cluster. The product distributions show preferential formation of the Cl(-) anion even though the formation of Cl(-)(H2O) would be favored thermodynamically. Although the structure of the HOO(-)(H2O) cluster resembles HO(-)(HOOH), we demonstrate that HOO(-) is the active nucleophile when the cluster reacts.

Alkyl radicals as hydrogen bond acceptors: computational evidence.

Spectroscopic, energetic and structural information obtained by DFT and G3-type computational studies demonstrates that charged proton donors can form moderately strong hydrogen bonds to simple alkyl radicals. The presence of these bonds stabilizes the adducts and modifies their structure, and gives rise to pronounced shifts of IR stretching frequencies and to increased absorption intensities. The hydrogen bond acceptor properties of alkyl radicals equal those of many conventional acceptors, e.g., the bond length changes and IR red-shifts suggest that tert-butyl radicals are slightly better acceptors than formaldehyde molecules, while propyl radicals are as good as H(2)O. The hydrogen bond strength appears to depend on the proton affinity of the proton donor and on the ionization energy of the acceptor alkyl radical, not on the donor-acceptor proton affinity difference, reflecting that the charge-transfer aspects of hydrogen bonding are particularly conspicuous when the acceptor polarity and basicity is low.

Hydrogen bonding to alkanes: computational evidence.

The structural, vibrational, and energetic properties of adducts of alkanes and strong cationic proton donors were studied with composite ab initio calculations. Hydrogen bonding in D-H(+)...H-alkyl adducts contributes to a significant degree to the interactions between the two components, which is substantiated by NBO and AIM results. The hydrogen bonds manifest themselves in the same manner as conventional hydrogen bonds, D-H bond elongation, D-H vibrational stretching frequency red shift and intensity increase, and adduct stabilization. The alkane adducts also exhibit elongation of the C-H bonds involved and a concurrent red shift, which is rationalized in terms of charge-transfer interactions that cause simultaneous weakening of both the O-H and C-H bonds. Like other dihydrogen-bonded adducts, the adducts possess a bent structure and asymmetric bifurcated hydrogen bonds. The hydrogen bonds are stronger in adducts of isobutane and in adducts of stronger acids. Intramolecular hydrogen bonding in protonated long-chain alcohols manifests itself in the same manner as intermolecular hydrogen bonding and can be equally strong.

Redshift or adduct stabilization--a computational study of hydrogen bonding in adducts of protonated carboxylic acids.

It is generally expected that the hydrogen bond strength in a D-H(***)A adduct is predicted by the difference between the proton affinities (DeltaPA) of D and A, measured by the adduct stabilization and demonstrated by the infrared (IR) redshift of the D-H bond stretching vibrational frequency. These criteria do not always yield consistent predictions, as illustrated by the hydrogen bonds formed by the E and Z OH groups of protonated carboxylic acids. The DeltaPA and the stabilization of a series of hydrogen bonded adducts indicate that the E OH group forms the stronger hydrogen bonds, whereas the bond length changes and the redshift favor the Z OH group, matching the results of NBO and AIM calculations. This reflects that the thermochemistry of adduct formation is not a good measure of the hydrogen bond strength in charged adducts, and that the ionic interactions in the E and Z adducts of protonated carboxylic acids are different. The OH bond length and IR redshift afford the better measure of hydrogen bond strength.

Reduction of 2-chloro-N-phenylpropanamide and 2-methyl-N-phenylaziridine with lithium aluminium hydride.

The reduction of 2-chloro-N-phenylpropanamide with LiAlH(4) has been re-examined. In contrast to previous findings, we obtain in almost equal quantities two amines from this reaction, namely N-propylaniline and the rearranged product N-isopropylaniline. 2-Methyl-N-phenylaziridine is an intermediate in the reduction and can be isolated from reactions with less LiAlH(4). Reduction of 2-methyl-N-phenylaziridine itself proceeds non-regioselectively to provide a mixture of propyl- and isopropylanilines. Formation of the amines by reduction of the aziridine is much slower than formation by reduction of the 2-chloropropanamide, which indicates that Lewis acid catalysis (by aluminium chlorohydrides) facilitates the reduction of the aziridine. In addition, Lewis acid catalysis increases the relative yield of the propylamine product. The reduction of 2-chloro-N-phenylpropanamide furnishes 2-phenylamino-1-propanol as a by-product, rather than the previously proposed 1-phenylamino-2-propanol.

Intramolecular hydrogen bonding and hydrogen atom abstraction in gas-phase aliphatic amine radical cations.

The intramolecular hydrogen atom abstraction by the nitrogen atom in isolated aliphatic amine radical cations is examined experimentally and with composite high-level ab initio methods of the G3 family. The magnitude of the enthalpy barriers toward H-atom transfer varies with the shape and size of the cyclic transition state and with the degree of substitution at the nitrogen and carbon atoms involved. The lower barriers are found for 1,5- and 1,6-abstraction, for chairlike transition states, for abstraction reactions in ionized primary amines, and for abstraction of H from tertiary carbon atoms. In most cases, the internal energy required for 1,4-, 1,5-, and 1,6-hydrogen atom abstraction to occur is less than that required for gas-phase fragmentation by simple cleavage of C-C bonds, which explains why H-atom transfer can be reversible and result in extensive H/D exchange prior to the fragmentation of many low-energy deuterium labeled ionized amines. The H-atom transfer to nitrogen is exothermic for primary amine radical cations and endothermic for tertiary amines. It gives rise to a variety of distonic radical cations, and these may undergo further isomerization. The heat of formation of the gauche conformers of the gamma-, delta-, and epsilon-distonic isomers is up to 25 kJ mol(-1) lower than that of the corresponding trans forms, which is taken to reflect C-H-N hydrogen bonding between the protonated amino group and the alkyl radical site.

Competing simple cleavage reactions: the elimination of alkyl radicals from amine radical cations.

Two different alkyl radicals can be expelled when unsymmetrical aliphatic amine radical cations undergo C-C bond cleavage. The branching ratio is strongly dependent on the internal energy of the reactant, even when the competition involves loss of closely related alkyl radicals. In mass spectrometers, the rate of loss of the smaller radical (excepting methyl) always exceeds the rate of loss of the larger close to threshold. The preference is reversed for the more highly energized ions that react in the ion source, demonstrating that the rate of loss of the larger radical rises much more rapidly with increasing internal energy than does the rate of loss of the smaller radical. This result is not easily reconciled with a simple RRKM model, given the expected strong resemblance between the transition states involved, whereas it agrees well with a description based on variational transition state theory. The heats of formation of the products determined with the G3 composite ab initio method show that loss of the smaller radical is without exception the more favorable reaction. The relative rates of the competing C-C bond cleavage reactions of the metastable ions vary with the number of degrees of freedom of the reactant, with the critical energy of the reaction, and with the difference between the heats of formation of the products. The presence of intermediate energy barriers when cleavage occurs at a branching point can give rise to variations in relative rates that are not easily interpreted.

Isotope effects on the unimolecular dissociation of ionized 3-methyl-2-butanol: reactions via a long-lived C-H-C hydrogen-bridged ion-neutral complex.

A pronounced isotope effect causes metastable CD3CHOHCH(CH3)2+* ions to expell C3H6D2 in preference to C3H7D in a ratio of approximately 33:1; a number of related compounds show similar effects. High-level ab initio calculations suggest that the reactant alcohol molecular ion possesses an extraordinarily long alpha-carbon-carbon bond and that the reaction proceeds via the formation of an intermediate hydrogen-bridged complex of propane and ionized vinyl alcohol, in which the bridging hydrogen atom is almost midway between the two carbon termini. The isotopic preference reflects the difference between the zero-point vibrational energies of the isotopically different product pairs rather than kinetic isotope effects on the hydrogen atom transfer reactions that precede dissociation.

Acyclic, achiral enamide nucleoside analogues. The importance of the C=C bond in the analogue for its ability to mimic natural nucleosides.

The conformations of an acyclic, achiral enamide thymidine analogue 1 have been studied by model building and geometry calculations, as well as by NMR NOE and UV experiments. The results indicate that there are no significant barriers to rotation around any of the sigma bonds, in particular the N1-C1' enamide bond, and that the analogue should be able to accommodate conformations that mimic the conformations of natural nucleosides in A- and B-type helices quite well. For comparison the saturated analogue 2 has been prepared and built into oligonucleotides. It is shown that incorporation of 2 in oligonucleotides results in a much larger depression of the melting temperature (deltaTm -10 to -12.5 degrees C) than does incorporation of 1 (deltaTm -5 to -6.5 degrees C).