Based on this understanding, computational tests for selectivity, reaction rate, and stability are developed and used to screen possible mimics of the natural product (–)-sparteine that can be synthesized in both antipodes. Derivatives of the bispidine and bispidinone structures are predicted to have high selectivity but poor stability on palladium. The strong trans effect of the carbene distinguishes the behavior of these complexes from other palla-.
Introduction and Methods
Background
- Roadmap
Construction of new bridges cannot proceed repeatedly, however they will not be permitted without a confidence in their performance that goes beyond the fact that the structures concerned have performed satisfactorily in the past. While direct or automated optimization is conceivable in cases of airfoil design or process engineering, an analytical approach is not even on the distant horizon of computational catalysis. A new, tunable ligand that could be easily synthesized in the (+) and (−) enantiomers would increase the substrate scope and allowable reaction conditions of existing (−)-sparteine protocols.
Methods
- Wavefunctions and Hamiltonians
- Building Up Chemical Information
The advantage of the force field is that it allows a dynamic description of a large number of atoms that can evolve by unexpected mechanisms. Increasingly accurate solutions are found using more sophisticated and flexible representations of the target wave function. In thermochemical investigations, it is necessary to take into account at least the majority of the correlation energy (the difference between the lowest Hartree-Fock and configurational interaction energy).
After mathematical simplifications and assignment of values for several parameters using an exact treatment of the He atom alone, a formula for the correlation energy of this general wave function in . The first derivatives of the energy with respect to the nuclear coordinates allow the determination of the minimum energy structures. Second derivatives of the energy help to locate transition states (saddle points on the potential energy surface) and can be analyzed to give the vibrational spectrum of a structure.
Solvent representation must be included when modeling reactions that take place in solution if more than qualitative insight is desired. However, the derivatives of the new Hamiltonian include the forces on the atoms due to the solvent, so that solvent-optimized structures can be determined. The rate constants of the basic steps are based on the free energy change between the transition state and the preceding stable intermediate containing all the same atoms.
This information must be gathered from the relative free energies of the various intermediates and any reaction orders observed for reactants.
Enantioselective Oxidation of Secondary Alcohols by
- Introduction
- Methods
- Mechanism
- General
- Chloride vs. Acetate
- Selectivity
- General
- Solvent Effects
- Substrates and Anions
- Thermodynamics
- Other Approaches
- Conclusions
Basic additives such as Cs2CO3 have been found to accelerate turnover [39], presumably by aiding alcohol deprotonation. The importance of structure 8 as an intermediate is supported by the recent x-ray characterization of an analogous species (in which the methyl group of the substrate is fluorinated) with the same structure [46]. A 5-coordinate transition state was sought in which the Cl atom remains bound and the β-hydrogen approaches Pd from out of the square plane.
52], whose observations of the same model reaction support strong rate limitation by either deprotonation (at low sparteine loading) or β-hydride elimination (at high sparteine loading). First, transition state energies are lower when the anion is displaced to the open face of the ligand (below Pd in Table 1) than when it moves to the occluded face (above Pd). Whether the oxygen of the substrate binds to the left or right site on Pd is another factor.
Thirdly, as mentioned, it requires more energy to displace the anion towards the aryl group in the substrate than to displace it towards the methyl group. Although possibly due to a difference in activation entropies of enantiomers, this more subtle effect may also be mediated by the response of the displaced anion to more polar solvents. Together, these two effects allow the solvent to influence the effective size and position of the X group.
Oxidation rates of substituted benzyl alcohols in the presence of excess sparteine were observed to increase with the strength of the electron-donating substituent [38]. The mechanism for the oxidation of sec-alcohols by ((–)-sparteine)PdX2 compounds starts with a simple exchange of the alcohol for an anion, followed by deprotonation of the bound alcohol. When the rate of β-hydride elimination that follows becomes rate-limiting, the enantioselectivity exhibited by the catalyst in the presence of the racemic substrate is a function of the relative energies of the set of diastereomeric structures of the βHE transition state.
New Ligands for Enantioselective Oxidations: Sparteine Mimics
Search Strategy
- Computational Assays
- Candidates
The first attempt to identify a synthetic substitute for sparteine was based on the idea that any difference between the proposed catalyst system and the established protocol based on (–)-sparteine would encourage new mechanisms for catalyst deactivation, unselective reaction, or other unwanted side reactions. effects that would take time to understand and alleviate. Therefore, we searched for a catalyst as similar as possible to ((–)-sparteine)PdX2, which would follow the same mechanism. Using what we have learned about the ((–)-sparteine)PdX2 catalyst (i.e., that under base-rich conditions that increase the rate selectivity of the reaction is determined by the disproportion between the activation barriers for β-hydride elimination to which encounter (R) and (S) alcohols and that the anion plays a key role in the βHE transition states) Equation 2.1 was used to predict the potential enantioselectivity of the ligands (in reactions with 1-phenylethanol in toluene at 60 °C.
Simulations with (–)-sparteine showed that accurate prediction of selectivities requires that transition states be optimized with the solvent model, while the faster approach could be in error by a factor of 2. The exothermicity of replacing the proposed ligand with (–)-sparteine was used to to measure the relative stability of the L2PdCl2 complex (a positive value indicates improved stability). Known ((–)-sparteine)Pd complexes have not been shown to suffer from degradation, so acceptable values for this parameter were not known a priori.
In studying the ((–)-sparteine)Pd(OAc)2 catalyst, βHE from a monodentate sparteine complex was found to be energetically (if not kinetically) competitive with the enantioselective pathway. A ligand less rigid than (–)-sparteine could allow reactant flux through this non-selective mechanism. 1 and similar ligands designed by Beak et al. [60] showed different enantioselectivities as a replacement for (–)-sparteine in asymmetric lithiations.
Although the ligand successfully catalyzed several asymmetric lithiations with enantioselectivity similar (but opposite) to (–)-sparteine, the kinetic resolution of 1-indanol yielded an sexp of 3.92, half that of (–)-sparteine[31 ].
Theoretical Results
For convenience, the relative energies of the three staggered conformations of one of these bonds in L2PdCl2 complexes were evaluated (Figure 3.7). Since the hydrogen substituents in both stereocenters of the configuration are on the same face of the palladium square plane, the environment around the palladium is roughly of CS symmetry. A fourth geometry in which both chiral arms have rotated was found to be 11.8 kcal/mol less stable than a.
A t-butyl group was found to be less effective as a molecular inhibitor than phenyl: in the case of ligandl, the b configuration is more stable. The typical βHE activation energies for the bispidine framework are fortunately similar to that calculated for sparteine. The electronic properties of the ligands affect this barrier as discussed, while the sterics by design interfere with the anions and substrate in a manner similar to sparteine.
The possibility of unselective reaction is closely related to a ligand's stability since one of the Pd-N bonds must be broken during this alternative β-hydride elimination. Most importantly, these ligands were predicted to be able to match the selectivity demonstrated by (–)-sparteine catalysts. The chiral arms of candidates g and h were calculated to prefer more than three kcal/mol (see Figure 3.7), and in this geometry were predicted to exhibit selectivity factors of 14 and 26, respectively, in kinetic resolutions of 1-phenylethanol.
The success of (–)-sparteine (and the failure of other apparently well-suited ligands) in distinguishing antipodes is based on volume exclusion: the shape of the ligand/metal/anion complex at the moment of βHE makes it allows substrate to assume its ideal geometry in the transition state, while forcing its enantiomer into a slightly distorted geometry.
Experimental Results
Since the anion is pushed into the high potential energy region, the (S) enantiomer must overcome an activation barrier that is 3.6 kcal/mol higher than the (R) enantiomer in the case of ligandium. The potential for long-range electrostatic interactions can be useful in designing ligands based on more stable frameworks. Unlike (–)-sparteine, the formation of the o ligand and (H3CCN)2PdCl2 precursor is not exothermic.
The lack of multiple fused rings in the proposed ligands also allows the inner piperidine rings to reverse and adopt the "boat" conformation, as in casec. The Pd(OAc)2 complex of o is predicted to be even less stable compared to the acetate complex of (–)-sparteine. Clearly, if bidentate ligands of this type are to be successful, a way must be found to improve their stability.
3.4 2nd Generation (–)-Sparteine Mimics
Our interest in phosphine ligands was therefore tentative, but due to the strength of the P-Pd bond we considered some models. The group b ligands in Figure 3.12 show that replacing the nitrogen atoms of the bispidines with phosphorus actually gives ligands with superior stability. This means that while the N-C∗bonds of the bispidines direct the stereocenters slightly "down" towards the palladium (Pd-N-C∗angles 111◦), the stereocenters attached to the phosphorus are directed away from the reacting substrate (Pd-P-C∗angles 114◦–117 ◦).
Second, the greater length of P-C bonds leaves the rotation of the stereocenter unimpeded by the ligand backbone. Another approach to improve the stability of the bispidines was to reduce the steric bulk of the pocket where palladium must bind. In ligandsp andq (Figure 3.13), one of the stereocenters is replaced with a methyl group or hydrogen. pawn-related C1-symmetric molecules were synthesized by Beak, et al.[60]) That the exchange of pawn (–)-sparteine on PdCl2 is thermoneutral in agreement with the fact that the two ligands have carbon atoms in the same surrounding positions.
Finally, a combination of the stability of phosphines and the potential selectivity of the bispidines was sought. Ligand s illustrates another novel concept for using the ligand's structure to direct the selectivity of a reaction. Specifically, one side of the ligand is better suited to host the anion during βHE, and one site on Pd is favorable for binding the alcohol.
The shape of the ligand (or ligand-anion combination) is responsible for both of these factors.
