SECRETARIA DE TRABAJO Resolución 1336/2014

Introduction

From our results of previous chapters it is fascinating to consider the applicability to consider the dynamic effect idea for other alkene hydroborations. However, this could be an arduous task. To explore the impact of dynamics on more highly substituted alkenes we selected a representative group of disubstituted and trisubstituted alkenes.

The regioselectivity of hydroborations of highly substituted alkenes compared to that of less substituted alkenes has been of interest since the discovery of hydroboration. The reactivity and selectivity for hydroborations of highly substituted alkenes are generally explained using sterics as the predominate factor. In more detail, the kinetic selectivity in hydroboration is viewed as the result of the two differing transition state barriers that lead to the alternative products. This has been applied without considering the fact that an exothermic association process with a free energy barrier might be involved and this association free energy barrier could be the rate-limiting step. The combination of the rate limiting association and the potential role of dynamic effects provides a new mechanistic interpretation of experimental observations of experimental reactivities and selectivities with highly substitutive alkenes.

These remarks leave some essential questions: Is there a discrepancy between the experimental selectivity and transition state theory for the hydroboration of highly

substituted olefins with BH3? If so, do dynamic trajectories account for the observed selectivity?

To test this, high level calculations were used to predict the ΔΔG‡

from the two transition states leading to the regioisomeric products. This let us know if the experimental ratio is what would be expected by transition state theory. An accurate computational approach is necessary. From previous examples we examined a large combination of ab initio or DFT methods and basis sets for their ability to model the potential energy surface for addition of BH3 to propene, as judged by comparison with CCSD(T)/aug-cc-pvtz energies.me

The B3LYP/6-31G* calculations performed the best among DFT functionals / basis sets tested for geometry optimizations and trajectory calculations. This means that B3LYP/6-31G* would be a good choice for trajectory calculations and it also means that composite methods that are built on B3YLP geometries should be good for determining energies. This is what was found for accurate energies, G3B3 energies performed very well matching CCSD(T)/aug-cc-pvtz with in 0.1 Kcal/mol. For this reason, G3B3 calculations were selected for the study of the larger hydroboration reactions.

Theoretical Pathway in the Reaction Model of the Hydroboration of Trans-2- butene with BH3

The kinetics of hydroboration of trans-2-butene were studied by Brown in 1984.88 For these studies he started with the borinane dimer (R2HBBHR2). He found that most

monomer-dimer dissociation equilibrium is fast and that the rate-limiting step is the reaction of the monomer with the alkene as seen in the previous case of 9-BBN. Brown considered that this mechanism of hydroboration with dimeric monofunctional boranes was general. Brown also observed that the hydroboration of cis-2-butene is faster than the corresponding reaction with trans-2-butene. The rationalization for the difference on the reaction rate, 5.40 for cis-2-butene and 3.55 for trans-2-butene, is that there is relief of strain in the transition state for hydroboration of the cis-alkene. This is notable because it is the hydroboration transition state and not an association transition state is supplying the rationalization for the observation.

When chiral dialkylboranes are used for the hydroboration of disubstituted alkenes, there can asymmetric induction in the generation in the product alcohol. Trans- 2-butene is a prochiral alkene that was used to determine the potential for asymmetric hydroboration with a variety of enantiomerically pure boranes.

The historical importance of hydroborations of trans-2-butene makes it an important subject for our study of the potential role of dynamics in the selectivity of hydroboration reactions. In the simple hydroboration of trans-2-butene no regioselectivity was involved. Our purpose was to explore this prototypical reaction to the reaction energetics if the free energy barrier for association as opposed to the actual hydroboration step is rate-limiting.

Table 4.1. Enthalpies and free energies for calculated structures in the hydroboration of trans-2-butene with BH3.

The energies are relative to the starting materials and is expressed in Kcal/mol. The enthalpies and free energies are calculated at 25 deg. C.

In gas-phase B3LYP with both 6-31+G** or 6-31G* in these calculation’s basis set, we located the π-complex 4a-2 and hydroboration transition structure 4a-3‡ _{for the}

hydroboration of trans-2-butene with BH3 were located. For the structures found the

calculations. The complete list of the calculated enthalpies and free energies for each method and structure are shown in Table 4.1 relative to the separate starting materials.

Our discussion will focus on the most reliable G3B3 energies. The calculated enthalpic barrier between the complex and the product formation transition state is only 0.9 kcal/mol. The formation of complex 4a-2 from BH3 / trans-2-butene is enthalpically

barrierless. However, such association reactions always involve an entropic barrier. Within variational transition state theory, the variational transition state for such a process is when the free energy reaches a maximum along the free energy path. We proceeded to search for this variational transition state.

The starting point for the location of variational transition state 4-a4‡ was the optimized structure found in a scan of positions with BH3 and trans-2-butene centroids separated by 5 Å. From this structure, a steepest-descent path in mass-weighted coordinates was followed. The steepest-descent path was obtained using a modified version of PROGDYN83,84, in which no momentum is given to nuclei and very small steps (< 0.00025 Å) are used, varying the size of the steps continually to avoid oscillations. This approach has the problem of being extremely slow compared to other approaches, but it has the virtue of being extremely reliable. The steepest decent path was obtained using a modified version of PROGDYN as described in previous chapters. For every 40th structure along the steepest-descent path, the free energy was calculated the variational transition state structure 4a-4‡ was identified the free energy maximum along this path that exhibited greater than one imaginary frequency. Having the energetics we can generate a reaction coordinate graph stopping when it finds a

minimum, in this case complex 4a-2. From the graph we can easily find any barrier is present between starting materials and complex.

Figure 4.1. Enthalpy and free energy reaction coordinate diagrams for the hydroboration with trans-2-butene with BH3.

For the hydroboration of BH3 / trans-2-butene we found the variational transition

structure 4a-4‡. The complex 4a-2 is enthalpically 11.7 kcal/mol below the separate starting materials and it is 9.4 kcal/mol below the variational transition state 4a-4‡. As a result the complex 4a-2 is formed with significant excess energy. The barrier for formation of product 4a-5 from 4a-2 is only 0.9 kcal/mol so the excess energy present in 4a-2 is much more than is needed to overcome the barrier for product formation. As a result, we can conclude that, significant excess energy is thus available from the formation of 4a-2, and the barrier for formation of product 4a-5 from 4a-2 is small. As was the case for propene, the formation of product may be faster than a thermal

equilibration with the solvent. The reaction coordinate diagram for the reaction is shown in Figure 4.1.

As in other cases we explored the effect of an anharmonic correction on the energetics. The anharmonic corrections change the energies modestly and interestingly bring the free energy for reaction from the complex over the product forming transition state down somewhat. This makes the prospects for dynamic effect in these reactions even greater. The free energy barrier starts out at about 2.5 kcal/mol and after inclusion of the anharmonic correction the free energy barrier goes down to about 0.8 kcal/mol. Of course in the case of trans-2-butene there is no regioselectivity to be affected by a dynamic affect in the reaction, but it may be of interest in future studies to determine if an isotope effect can be observed in this reaction that would be the result of a dynamic effect.

Table 4.2. Calculated free energy after anharmonic adjustment for the structures located.

According to methods/basis sets; G3B3, B3LYP/6-31G* and B3LYP/6-31+G** calculations, they are relative to the starting material and expressed in kcal/mol.

Table 4.2 lists the corrected energies for the transition structure 4a-3‡ and complex 4a-2, form this analysis we can observe that barrier for the formation of the product is 1.2 kcal/mol instead of the 1.4 kcal/mol. From the analysis we also determined that the difference in energy between the variational transition state 4a-4‡ and the complex 4a-2, was 6.2 kcal/mol compared to the 6.7 kcal/mol predicted without corrections.

To summarize, from the theoretical reevaluation of the mechanism of hydroboration of trans-2-butene, we find the reaction precedes though an exothermic association process and that there is no enthalpic barrier for this association. The entropic barrier leads this association to be the rate-limiting step in the reaction. The low energy of the complex compared to separate starting materials will mean that there is excess energy in the complex on its formation and the low energy of the barrier going on from the complex suggest that the rate of product formation from the complex with its excess energy will be subject to a dynamic effect

Intramolecular H/D Isotope Effect For The Hydroboration of Tetramethylethylene with BH3

In an older mechanistic study Pasto studied a series of isotope effects for hydroboration of tetramethylethylene with BH3 and included intermolecular hydrogen-

deuterium isotope effects on the absolute rate, intramolecular hydrogen-tritium isotope effects on product formation, and competition 10B/11B kinetic isotope effects. The hydrogen-deuterium KIE on the absolute rate observed by Pasto was 1.18. Pasto

interpreted this value as a superposition of a primary and secondary isotope effect. Pasto expected that a primary isotope effect would have a value greater than unity while a secondary isotope will be less than unity.89 Because the 1.18 value was lowered by the assumed significantly inverse secondary isotope effect, Pasto did not recognize that the unusual character of the small isotope effect for a reaction in which hydrogen is being transferred. Normally if hydrogen is transferred during a rate limiting step the hydrogen-deuterium isotope effect would be greater than 2. It should be recognized at the time, the ideas related with an association transition state being a variational transition state and rate limiting had not been developed. Pasto could not have easily interpreted his small isotope effect in any other way. Pasto observed an intramolecular isotope effect on H/T of 3.3, this was interpreted of reflecting the normal isotope effect for the hydroboration step without any inference from an inverse isotope effect. Pasto then noted that after an allowance between hydrogen and tritium the 3.3 agrees reasonably well with KIEs observed with 1-hecene and styrene in reactions of these alkenes with a monochloroborane in THF.89

The hydrogen-tritium isotope effects are intramolecular isotope effects that decide rather the product contains a hydrogen or tritium. In general, intramolecular isotope effects reflect the first irreversibly unsymmetrical step in a mechanism and this is not the rate-limiting step. The intramolecular isotope effect observed by Pasto decreased with increasing substitution on the double bond as well as with increasing substitution on the boron. Pasto interpreted these isotope effects as consistent with the decrease C-H bond formation and a B_H bond breaking in the transition state due to steric factors. He

also concluded that the observed isotope effect is not consistent with a secondary isotope effect arising from the formation of a π-complex between the borane and alkene in the rate-determining step.

The isotope effect of 10_B/11_{B was measured and Pasto deduced that an}

intermolecular competition between H and T was present and resembles the isotope effect for the product-determining step. The results Pasto obtained led him to believe that the isotope effect increased very slightly with increasing substitution on the double bond. He thought that this is consistent with an increase in the bonding interaction between the boron and carbon to the increase in the π-electron density of the double bond. Pasto concluded that the electronic effect offset the steric effect that would otherwise help to decrease the isotope effect as the degree of substitution on the double bond increased. It was thought the combination of the hydrogen-tritium and 10B/11B isotope effects suggests that C-H and C-B bond formation and B-H and C=C bond breaking occur in concert during the formation of a four-centered transition state. This interpretation is strained by the necessity by postulating a large inverse isotope effect that counterbalances the normal isotope an enormous in order to get to Pasto’s absolute effect of 1.1. We will see in the work described the isotope effects become more consistent with the new experimental KIE’s that we will present.

The hydroboration of tetramethylethylene on a 1:1 molar basis to afford thexylborane is a commonly employed synthetic procedure. After oxidation to afford tetramethylethylene, the ratio of 3H to 3D was determined in two ways. The first way employed 1

H NMR, taking advantage of a vicinal isotope effect of deuterium on the chemical shift of the isopropyl methyls of the product from the hydroboration of tetramethylethylene, leading to resolution of high-frequency signal of the isopropyl group doublet of 3H. The corresponding signal for 3D is unresolved but its amount was inferred by subtracting out the expected integration for 3H from the integral of the overlapping signals. A more satisfactory direct measurement was obtained from 13

C NMR analysis of the product from the hydroboration of tetramethylethylene. Employing conditions suitable for 13

C NMR integration,48

the fully resolved singlet and triplet signals for the methene carbons of 3H and 3D, respectively, could be integrated to determine the ratio of the isotopologs. From five measurements (three by the 1_{H NMR} process, two by the 13

C NMR process, the isotope effect was 1.24 ± 0.06. From the five measurements of the ratio of 3H to 3D gave values 0.635, 0.625, 0.611, 0.616, and 0.630. This leads to an 3H : 3D ratio of 0.624 ± 0.012. By taking the ratio to that determined for the stock solution (0.502 ± 0.024) and propagating the errors in a standard way, the isotope effect was 1.24 ± 0.06. This isotope effect is somewhat larger than what we observe in the hydroborations of 1-octene, styrene, and 2-methyl-2butene, but it is still a quit small isotope effect; within the conventional interpretation of isotope effects of greater than 2. At 1.24 there is some suggestion of hydrogen versus deuterium making some difference, but not a great amount of difference. It seems possible that this

could result from an reaction in which the selectivity was determined in a combination affects that we have proposed for the hydroboration of propene. For that proportion of the reaction that is governed by transition state theory, the isotope effect should be relatively large and that would tend to raise the overall kH/kD for a portion of the isotope effect that arose from direct trajectories, one might expect the isotope might be small. There then could be in vision to that the isotope effect in the case of tetramethylethylene results from a combination of these two possibilities. This interpretation suggests that with tetramethylethylene there is a larger portion of products formed by a process that is approximately controlled by transition state theory. Then is the case in the hydroborations of the other alkenes. Nonetheless the isotope effect is too small for the conventional mechanism to be the predominate pathway.

Isotope Effects, Dynamics, and the Nature of Selectivity in the Hydroboration of 2-

Methyl-2-Butene with BH3

The regioselectivity for the hydroboration of 2-methyl-2-butene is notably greater than that observed with a monosubstituted alkene. Brown attributed this selectivity to a powerful directive effect of sterics at the transition state.14

Brown explored the rate and stoichiometry for the hydroboration of 2-methyl- 2butene with BH3 in detail. This reaction stops at an earlier stage than the hydroboration of monosubstituted alkenes. The trialkylborane is formed at a very low rate and Brown reported a procedure for the selective synthesis for the disiamylborane. Such dialkylboranes are not obtainable in hydroborations of monosubstituted alkenes. The synthetic value of disiamylborane is that it is a highly selective hydroborating agent. According to Brown’s synthetic study, once Disiamylborane is formed the third hydroboration to form tridisiamylborane is only 40% complete after 24 h. The regioselectivity observed under normal circumstances in the hydroboration of 2-methy- 2-butene with BH3 is a composite of only two steps hydroboration by and hydroboration by RBH2.. In our studies, we have measured the selectivity for the BH3 reaction by the approach of using a very large excess of BH 3. This approach is designed to minimize the contribution designed to minimize the contribution of hydroborations by the monoalkylborane to the selectivity.

The process used to examine the regioselectivity of hydroboration of monosubstituted alkenes that was described in a previous chapter runs into some problems in the case of 2-methyl-2-butene and was modified. One problem explained previously was that small amounts of impurities in the BH3-THF, for example from THF decomposition, could interfere with the analysis. This problem is a greater determent in the study of the hydroboration of 2-methyl-2-butene since the amount of the minor regioisomers obtained in the reaction is very small. In addition, unlike in the case of the monosubstituted alkene, the study of the regioselectivity for the hydroboration of 2-

methyl-2butene cannot take advantage of deuterated starting materials for the direct observation for the selectivity. A disappointing attempt to clearly identify the chemical shifts of the products by 2

H NMR was investigated by synthesizing the Markovnikov alcohol though a different route. The volatile 2,2,3-trimethyloxirane was successfully prepared.90

Subsequently, the crude product with some solvent traces was put forward for the ring opening reaction with LiAlD4 to obtain the desired product as determined by 1

H NMR.

Scheme 4.3.

Despite the fact that the product was obtained, it was not completely pure and the purification process would have been time consuming due to the volatility of the

product. At last, not a clear chemical shift was obtained. In spite of this, by this point we had completely distinctive approach in mind to solve the challenge.

The use of a different ligand (BH3•SMe2 as opposed to THF) is a complication because some papers have proposed that BH3 is directly transferred from the ligand.67

As we have noted previously, the weight of evidence in the literature favors a more of an SN1 mechanism in which the BH3 is free prior to reacting with the alkene. It is notable that small regioselectivity differences can be observed in hydroboration depending on the particular borane ligand being used. However, such regioselectivity differences can

potentially arise from the effect of varying contributions from reactions of BH3 versus alkyl or dialkyl boranes.