Current Organic Chemistry - Volume 14, Issue 15, 2010

This special issue is aimed to illustrate the key advances provided by the synergy between modern computational methodologies and experimentation in organic chemistry. The recent history of computer development and engineering has confirmed Moore's law, which states that the processing power of computers increases in an exponential rate. Such progress has allowed a revolutionary qualitative transition from simplified models that helped understand observations to simulations that accurately predict the outcome of experiments. The complexity of the chemical problems that can be tackled by computer simulation is rapidly increasing and the size of molecules that can be modeled has rapidly grown from the humble diatomics to the exciting new fields of biomolecules or nanoscale materials. In this thematic issue nine reviews are presented in which the state of the art in the intersection of computational simulation and experimentation in organic chemistry is displayed. Renowned specialists in the field present a personal and thorough perspective on several topics where interplay between computation and experiment is essential. Prof. Cremer opens this special issue with a comprehensive study on how molecular vibrations affect the chemical bond properties, ultimately defining transition states and reaction mechanisms. Prof. Tantillo expands on the ubiquitous Nazarov reaction and illustrates yet another case of profitable interaction between experiment and computation. The peculiar electronic properties of the transition states of double group transfer reactions are presented by Dr. Fernandez and Prof. Cossio. Prof. Wentrup provides a broad and thorough revision of the chemistry of the cumulene carbon, including rearrangements of allenes, ketenes, isocyanates and other derivatives, allying simulation and bench work. Prof. Yañez defies our chemical intuition with striking results of acid-base chemistry in the gas phase that challenge conventional wisdom. Dr. Alonso-Gómez offers a detailed, didactic, tutorial-review on how to employ NMR, ECD, VCD, and ORD spectroscopy and molecular simulations to determine relative and absolute configurations in natural products. Expanding on this same line, Prof. Norrby introduces his Q2MM methodology, and its application to predict stereoselective reactions. Dr. Silva shows results on the development of novel synthetic tools from iteration between experiment and molecular modeling. Finally, Prof. Birney closes this special issue describing situations in which sequential transition states can be found along the mechanism of an organic transformation. The kinetic consequences of these rare potential energy surfaces are discussed. Given the quality of the articles and the commitment of all the authors to make a remarkable contribution to this compilation it has been a great pleasure to edit this special issue of Current Organic Chemistry. I hereby thank all the authors for their collaboration in the assembly of this issue that I hope it reaches the broad organic community and motivates new joint ventures between experimentalists and computational organic chemists.

The vibrational motions of a molecule in its equilibrium or during a chemical reaction provide a wealth of information about its structure, stability, and reactivity. This information is hidden in measured vibrational frequencies and intensities, however can be unraveled by utilizing quantum chemical tools and applying the Cal-X methods in form Vib-Cal-X. Vib-Cal-X uses the measured frequencies, complements them to a complete set of 3N-L values (N number of atoms; L number of translations and rotations), derives experimentally based force constants, and converts them into local mode stretching, bending, and torsional force constants associated with the internal coordinates describing the geometry of the molecule. This is done by utilizing the adiabatic vibrational mode concept, which is based on a decomposition of delocalized normal vibrational modes into adiabatic internal coordinate modes (AICoMs) needed to describe bonding or changes in bonding. AICoM force constants relate to the intrinsic bond dissociation energy (IBDE) of a bond and, accordingly, are excellent descriptors for bond order and bond strength. It is shown that bond dissociation energies, bond lengths, or bond densities are not directly related to the bond strength because they also depend on other quantities than just the bond strength: the bond dissociation energy on the stabilization energies of the fragments, the bond length on the compressibility limit distance between the atoms, the bond stretching frequency on the atom masses, etc. The bond stretching force constants however lead directly to bond order and bond strength as has been demonstrated for the bonds in typical organic molecules. Using this insight, the generalized vibrational frequencies of reacting molecules are used to obtain insight into the chemical processes of bond breaking and forming. An elementary chemical reaction based on these processes is characterized by a curved reaction path. Path curvature is a prerequisite for chemical change and directly related to the changes in the stretching force constants as they respond to the bond polarizing power of a reaction partner. The features of the path curvature can be used to partition the reaction path and by this the reaction mechanism in terms of reaction phases. A reaction phase is characterized by an elementary structural change of the reaction complex leading to a chemically meaningful transient structure that can convert into a real transition state or intermediate upon changing the environmental conditions or the electronic structure (substituents, etc.) of the reaction complex. A unified approach to the study of reaction mechanism (URVA: Unified Reaction Valley Approach) is discussed that is based extensively on the analysis of vibrational modes and that is aimed at detailed understanding of chemical reactions with the goal of controlling them.

Pentadienyl cation electrocyclizations have played key roles in the syntheses of many complex organic molecules. Herein, theoretical studies on the mechanisms of pentadienyl cation electrocyclizations are reviewed and general principles applicable to the design of such reactions are highlighted.

In this article, recent computational studies focused on double group transfer reactions and related processes are summarized. The reported results clearly indicate that these transformations can be considered as a subclass of pericyclic reactions occurring concertedly, with high activation barriers and synchronicity values, and through highly symmetric transition states. Interestingly, the aromatic nature of the latter saddle points has been also studied and discussed showing that they can be viewed as the in-plane analogues of sixmembered hetero-aromatic rings. Finally, the application of the so-called “Strain Model” on these important processes has demonstrated that the strain (the energy required to deform the reactants to the geometry they present in the corresponding transition state) is the major factor controlling the high barrier heights in spite of the stabilizing contribution of the aromaticity.

Interconversions between α-oxoketenes, imidoylketenes and α-oxoketenimines, thioacylketenes and acylthioketenes, vinylketenes and acylallenes, isocyanates, and thioacylisocyanates and acylisothiocyanates take place by means of 1,3-shifts of substituents, which are facilitated by electron-rich migrating groups, especially those containing lone pairs on the migrating atoms. A bonding interaction between the lone pair orbital and the LUMO of the cumulene moiety stabilizes the transition state and can even make it become an intermediate. The 1,3-shifts can also be said to be pseudopericyclic reactions. The 1,3-migration of aryl groups is accelerated by electron- donating substituents in the phenyl ring. In general, for like substituents, migratory aptitudes decrease in the series α-oxoketene > imidoylketenes > acylallene > vinylketene.

An overview of recent studies, which show the important role played by computational chemistry in explaining and predicting the behavior of a great variety of systems is presented. The first example illustrates the useful interplay experiment-theory which allowed to unambiguously characterize the X2(CH3)7 + (X = Si, Ge, Sn, Pb) cations as paradigmatic examples of molecular systems involving pentacovalently bound carbon atoms. Also, the possibility of deeply analyzing the bonding in molecular systems, led to a rationalization of the quite different behavior of acetylene and iminoborane derivatives, in spite of being isoelectronic species. Similarly, the analysis of the bonding perturbations usually associated with ion-molecule interactions in the gas phase, or with protonation and deprotonation processes, has made possible the characterization of non-conventional complexes as the key structures in the interactions of unsaturated and aromatic Si and Ge containing compounds with transition metal ions or to explain the dramatic enhanced acidity of alkylboranes and α,β- unsaturated borane derivatives.

This minireview is addressed to readers with a background in basic organic chemistry and spectroscopy, but without a specific knowledge of NMR, ECD, VCD and ORD. Herein we summarize the role of quantum mechanical ab initio prediction of spectral properties in NMR and chiroptical spectroscopies. Illustrative examples of the application of prediction of chemical shifts and scalar couplings to the determination of chemical constitution and relative configurations of natural products are presented. Once the relative configuration is determined, the absolute configuration can be established with the help of ECD, VCD and ORD spectroscopies assisted by quantum mechanical prediction of the corresponding spectra. The scope, limitations and advantages of these chiroptical spectroscopies are presented, in order to help the reader in choosing a suitable combination of ab initio and spectroscopic tools when facing a particular problem.

Q2MM is a method designed to allow application of molecular mechanics calculations to transition states in chemical reactions. It is one of the few methods available that allow determination of a complete set of low-energy transition states for medium-sized systems, and thereby gives a unique opportunity to investigate kinetic selectivity, in particular stereoselectivity. The current review will give an outline of the procedure, an overview of the types of reactions that have been studied using this method, and summarize the factors affecting the accuracy of the results.

Collaborative work between experimentalists and computational chemists have demonstrated a stong synergy which allowed the rationalization of allenyl azide chemistry and permited the development of an efficient synthetic tool aimed at the preparation of several alkaloids. Saturated allenyl azides undergo a reaction cascade involving key diradical intermediates that follow the Curtin- Hammett model whereas unsaturated allenyl azides form indolidene intermediates that furnish the final indole products via electrocyclic ring closure events taking place out of the Curtin-Hammett regime. The regiochemistry of the reaction cascade with the latter substrates can be manipulated by Cu(I) addition to the reaction mixture.

Recent computational and experimental studies of organic reactions that show sequential transition structures on the potential energy surfaces are reviewed. The specific focus is on pericyclic and pseudopericyclic reactions. A distinction is made between symmetric and unsymmetric systems; in the former, the intrinsic reaction coordinate connects the two transition structures. The importance of the change in the reaction coordinate for establishing the existence of the second transition structure and the influence of the energy of the second transition structure on the barrier height of the first and emphasized. In this latter context, corners on a reaction pathway are also significant. Lastly, the merging of two sequential transition structures is shown to give an “effective monkey saddle” transition structure.