SECRETARIA DE TRABAJO Resolución 1339/2014

, eight afforded product. This is a significantly greater proportion then what was seen for trajectories started at the complex. These results suggest that the excess energy that is present when the complex forms from the association of the borane with the alkene would lead to some of the product being formed rapidly.

In summary, the calculated selectivity from transition state theory in comparison from the experimental selectivity provides no evidence for a dynamic effect in this hydroboration. However, the trajectory studies suggest that a substantial amount of product would be formed on a timescale that is faster than thermal equilibration. As a result it is possible that a possible match between transition state theory expected selectivity and the experimental selectivity is fortuitous. We will examine this issue again after a different probe of selectivity in this reaction, that of the kinetic isotope effect.

H/D Isotope Effect in the Hydroboration of 2-Methyl-2-butene

The hydrogen-tritium effect observed by Pasto was 3.01 to 3.25. In two measurements 10B/11B isotope effect with 2-methyl-2-butene Pasto observed KIE’s 1.044 ± 0.006 and 1.057 ± 0.006. As before these values were taken supporting a four- centered transition state. Other kinetic isotope effect experiments were calculated with and without the inclusion of KH/KD on monosubstituted [1-hexene, 9.59-10.00,10.85-

11.29; Styrene 10-.00-9.00, 10.44-10.35] and disubstituted [3-Hexene, 6.92, 8.73; 2- Octene, 7.38-8.89; 2-Ethyl-1-hexene, 7.47, 8.99; Propenylbenzene, 7.24, 9.01] with BH3

generalized, from the hydrogen-tritium and 10B/11B isotope effects, that the reaction proceeds through a unsymmetrical four-centered transition with C-H and C-B bond formation occurring in concert with B-H and C=C bond breaking, using as an example the description of the isotope effect for tetramethylethylene. Our isotope effect is not constant with Pasto’s, he measured a hydrogen-tritium isotope effect and we measured a hydrogen deuterium isotope effect. The difference that is observed is far outside of any understandable difference due to the isotope effects and there is simply a discrepancy between Pasto’s results and ours. As will be seen, we observed isotope effects that do not fit with Pasto’s observations.

Although borane will add twice to 2-methyl-2-butene to afford disiamylborane, the second addition is much slower than the first (ref to one of the Pasto papers I believe). As a result, when excess borane is used the isotope effect observed in the reaction should predominantly reflect simple borane addition. This advantage versus terminal alkenes like styrene is counterbalanced by the disadvantage that the B-H bonds of the borane cannot be reacted to completion with the 2-methyl-2-butene, precluding the generation of a direct isotopic calibration standard of the product 5. Instead, the ratio of H to D in the stock borane solutions used for these reactions was quantified by reacting the solution with excess 1-octene and determining the ratio of the deuterated versus non-deuterated 1-octanol product by integration of the resolved 13

C NMR signals of the two materials. The ratio of 4H to 4D was then determined directly from the 1

H NMR integration of the methene proton of 5 versus the methyl and isopropyl group signals.

It is clear that the KH/KD is not consistent with a normal primary H/D isotope effect. For the hydroboration of 2-methyl-2-butene with partially deuterated borane, four measurements of the H : D ratio in the stock solution by the process described gave values 0.480, 0.504, 0.515, and 0.508. The leads to H : D ratio of 0.502 ± 0.024. The six measurements of the ratio of 4H to 4D gave values 0.457, 0.485, 0.490, 0.446, 0.465, and 0.464, from three independent reactions. This leads to a 4H : 4D ratio of 0.468 ± 0.018. By taking the average of these ratios and propagating the errors in a standard way, the isotope effect was 0.93, and the 95% confidence range, treating each measurement as independent, was ±0.06. Because of the complications in this process, the reliable accuracy of this KIE measurement is unlikely to be better than ±10%. Accordingly, it is not clear that the kH/kD is really less than unity, but the isotope effect is small and the results are again not consistent with a normal primary H/D isotope effect.

Not all three independent reactions where prepared with the same ratios of borane to alkene. However, when using either 3 or 0.3 equivalents of borane to alkene, the measurements where analogous. This is due to the fact that the trialkylborane is not likely to be formed.

Scheme 4.5.

To ensure that the observed isotopic ratio was the result of kinetic rather than thermodynamic process, a control experiment was carried out in which the

hydroboration of 2-methyl-2-butene was first conducted with 3 equiv of BH3, then 3 equiv of BD3 was added. After 12 h at 22 °C, the reaction was worked up oxidatively and the 4 was analyzed for deuterium content. None could be detected by 13

C NMR. The small KH/KD suggest that a dynamic effect does play a role in the hydroboration 2-methyl-2-butene. The suggestion from this observation is that the math up of transition state predictions theory with observed selectivity is fortitudinous. In an isotope effect the competing possibilities are traveling over the same energy surface and the isotope effect arises from zero point energies and other factors that is normal. It would be unusual for a dynamic control process to mimic the zero point energy factors involved in an isotope effect. Looking at the regioselectivity, a dynamic control process still has to cross-differing heights of barriers in order to get to a completive form of product. Under those circumstances it is easy to envision an accidental agreement of transition state theory with experiment. These ideas suggest that isotope effects may be a more sensitive probe for dynamic effects than product regioselectivities.

Calculated Pathway for the Hydroboration of 1-Methylcyclohexene with BH3.

The investigation of the hydroboration of more substituted olefins included the study of cyclic alkenes. Brown’s study of cycloalkenes including 1-methylcyclohexene lead to the generalization that hydroboration proceeds through a cis-anti-Markovnikov addition of the B-H bond to the alkene. This hydroboration is very selective affording

trans-2-methylcyclohexanol from the hydroboration of 1-methylcyclohexene. Brown

methylcyclohexene compared to 72 for cyclopentene and 100 for 1-hexene. In Brown’s studies he noted isomerization on heating. To judge the scope of the isomerization he made use of cyclic alkenes. His experiments found that the boron was equilibrated on all of the available sites and tends to accumulate on the least hindered carbon. Brown developed a procedure to displace organic boranes to form cyclic alkenes proving to effectively convert exocyclic alkenes to endocyclic. An interesting example of this displacement procedure came with an adduct of 1-methylcyclohexene. By adding 1- hexene and diglyme to the dialkyl adduct the methylcyclohexyl group was displaced to give a product ratio of 77:23 1-methylcylohexene to 3-methylcyclohexene. Most relevant for our research Brown reported the product ratio for the hydroboration of t methylcyclohexene afforded 0.8% of the cis-2-cyclohexanol, 1.5% 1- methylcyclohexanol, and 97.7% of the trans-2-methylcyclohexanol preferred. The observation of the cis-2-methylcyclohexanol is interesting. It is indicative of either isomerization occurring, under Brown’s reaction conditions, or the presence of impurities in the started alkene. We were interested in the effect of the cyclic alkene on the potential role of dynamic effects in hydroborations and sought to compare the energy surface for cyclic alkenes versus analogous acyclic alkenes. In this case we were able to compare the hydroboration of 1-methylcyclohexene with that of 2-methyl-2-butene. Later we will make a comparison with the hydroboration of 2-methylcyclohexene.

The most pertinent information for our research the findings reported for product ratio after the hydroboration of 0.3 mol of olefin with 0.125 mol of borane in diglyme. The outcome was analyzed to be 0.8 % of the cis-2-methylcyclohexanol, 1.5 % of 1-

methylcyclohexanol and 97.7 % of the preferred trans-2-methylcyclohexanol (Scheme 4.6).

Scheme 4.6

Our current investigation was intended to contribute to the theoretical pathway in the reaction model of the hydroboration of 1-methylcyclohexene with BH3 with an

innovative prospective. Our hypothesis was to compare directly the barriers of a cyclic alkene and the acyclic analogous alkene, as well as, put side-by-side two different structural isomers of a cyclic alkene. In this case we were able to compare the hydroboration of 1-methylcyclohexene and 2-methyl-2-butene, and soon after we will make a comparison for the hydroboration of 3-methylcyclohexene.

A reaction coordinate diagram based on the calculated enthalpies and free energies is shown in Figure 4.3. We wanted to judge the experimental selectivity for the reaction against the predicted ΔΔG‡ for transition states. To accomplish this, the hydroboration transition structures for the 1-methylcyclohexene reaction were located in the gas-phase G3B3, B3LYP/6-31G* and B3LYP/6-31+G** calculations. The approximate ΔΔG‡ and ΔΔH‡ of all the structures found by the three different methods are presented in Table 4.6. For our discussion we will refer to the G3B3 energies. Based

on their close match with other high level calculational methods like CCSD(T) with very large basis sets the hydroboration of propene with BH3 (Chapter II).

Figure 4.3. Reaction coordinate diagram for the hydroboration of 1-methylcyclohexene based on the predicted G3B3 enthalpies and free energies.

Two differences in energy had to be considered in this case to compare with experimental regioselectivity. Allowing for the shared like conformation of the 1- methycyclohexene there are two faces for the approach of the BH3 to the alkene it is necessary to consider the difference of energy anti-Markovnikov transition state and Markovnikov transition state for the BH3 attack at each. The ΔΔG‡ predicted for

structure 4d-4‡ and 4d-6‡ is 2.6 kcal/mol and the ΔΔG‡ predicted for structure 4d-5‡ and 4d-7‡ is 2.7 kcal/mol. The relative energetics for these structures are represented in Figure 4.3. Preference for anti-Markovnikov can be consider in agreement with the

experimental percentage reported in the literature of (97.7 % and 0.8 %) 98.5 to 1.5 anti- Markovnikov to Markovnikov. Its notable that with both of the trisubstituted alkenes investigated the experimental product ratio matches up well with the theoretical calculations.. A difference between the two systems is that the π-complex 4d-2 or π- complex 4d-3 to the transition structure 4d-4‡ is 3.7 kcal/mol with 1-methyl cyclohexene with the corresponding barrier in 2-methyl-2-butene was lower at 3.0 kcal/mol. The difference in the barriers can be expected to reflect the consequences of the afforded experimental selectivity. In fact 1-methylcyclohexene is slightly more selective than 2- methyl-2-butene when judging the anti-Markovnikov versus Markovnikov product. The difference in energy for the two possible anti-Markovnikov transition states is very small, 0.3 kcal/mol, when the difference in energy for the two possible facial attacks to form the Markovnikov transition states is 0.5 kcal/mol.

Table 4.6. Enthalpies and free energies for calculated structures for the hydroboration of BH3 with 1-methylcyclohexene.

Table 4.6 continued.

According to methods/basis set G3B3, B3LYP/6-31G* and B3LYP/6-31+G**

calculations, they are relative to the starting material and expressed in kcal/mol. Energies are kcal/mol versus the separate starting materials

Table 4.7. Free energy for π-complexes at hydroboration transition states after anharmonic corrections.

The predicted barriers discussed so far have not included any allowance for corrections of any. Explained previously, we found essential to fix the calculated energetics by allowing for the second-order perturbative anharmonic contributions to the vibrational energies and entropy since the magnitude of the ΔΔG‡ is small side. For the π-complexes and product forming transition structures are shown in Table 4.7.

As a result of the anharmonic correction, the ΔΔG‡ predicted for structure 4d-4‡ versus 4d-6‡ changed to 2.4 kcal/mol and the ΔΔG‡ predicted for structure 4d-5‡ and 4d- 7‡ stayed at 2.7 kcal/mol. The uncorrected versus the corrected ΔΔG‡ for the competitive transition states can be found in Table 4.7. Over the anharmonic corrections did not change the basic situation that the calculated and experimental selectivities are in reasonable agreement. This fits within the finding that transition state theory predicts the experimental selectivity in the hydroboration of 2-methyl-2-butene.

The ΔΔG‡ _{predicted for the two anti-Markovnikov transition states, structures 4d-}

4‡ and 4d-5‡ when corrected is 0.5 kcal/mol. This value compares to the ΔΔG‡ predicted for the two Markovnikov transition states, structure 4d-6‡ and 4d-7‡, which after the correction is 0.8 kcal/mol. The difference in the ΔΔG‡ predicted after correcting for the perturbative anharmonic contributions is more consistent with the expected stability of the transition states according to the half chair attack preference. The difference in the energetics in the reaction of BH3 with 1-methylcyclohexene after anharmonic correction

Figure 4.4. Calculated ΔΔG‡ for transition states 4d-4‡ versus 4d-6‡, and, 4d-5‡ versus 4d-7‡ with and without the anharmonic contributions.

Overall, we find that the hydroboration of 1-methyl-cyclohexene is well predicted by transition state theory, as was the case in the hydroboration of 2-methyl-2-butene. A more apparent understanding of the consequences of including the perturbative anharmonic contributions when evaluating such little differences in energies was seen here.

Dynamics and Selectivity in the Hydroboration of 3-Methylcyclohexene with BH3

Calculated Pathway for the Hydroboratoin of 1-MethylcycolHexane with BH ₃ The stereochemistry of hydroboration reactions with borane has been studied for several cyclic and bicyclic alkenes. Brown determined the directive effect of allylic substituents on cyclic alkenes. When 3-methyl-cycylohexene was hydroborated with

diborane in tetrahydrofuran, a mixture of 49% 2-methylcyclohexanone and 51% 3- methylcyclohexanone, was obtained after oxidative workup follow by a Jones procedure.17b

Scheme 4.7

Brown found that selectivity increased little with a bulky hydroborating agent. When 3-methylcyclohexene was hydroborated with disiamylborane, after classic oxidation followed by further oxidation with a Jones procedure, the selectivity was 48% 2-methylcyclohexanone and 52% 3-methylcyclohexanone.

Subsequently, Brown was able to resolve the oxidized blend of alcohols with a diglycerol capillary column. It was confirmed that when 3-methylcyclohexene is hydroborated with a bulky hydroborating agent, disiamylborane, 48% of the boron was added to C-2 and 52% was added to C-1. From the 48% addition, 18% formed the cis-2- methylcyclohexanol and 30% gave the trans-2-methylhexanol.

Scheme 4.9

Brown generalized that the stereochemistry was not controlled by the stability of the product. The low experimental selectivity pointed by Brown for the hydroboration of 3-methylcyclohexene is striking and we explored this reaction further to establish if transition state theory fits with the experimental results. We sought to determine if is there a discrepancy between the experimental selectivity and transition state theory for this reaction. If so, do dynamic trajectories account for the observed selectivity?

Our initial goal was to establish the effect of excess borane on the product selectivity for the hydroboration of 3-methylcyclohexene. When this reaction done using 44 equivalents of borane•dimethylsulfide afforded, the product mixture after oxidation to the alcohol stage, was 47.9% of 2-methylcyclohexanol and 52.1% was 3- methylcyclohexanol. The 47.9% C-2 addition consisted of a combination of 8.4% of the

product was a combination of 28.4% of the boron addition to the C-1 position to be cis- 3-methylcyclohexanol and 23.8% of trans-3-methylcyclohexanol. The 52.1% of the C-3 addition consisted of a combination of 28.4% of cis-3-methylcyclohexanol and 20.83% of trans-3-methylcyclohexanol. When the reaction was performed with a larger excess of borane•dimethylsulfide, 100 equivalence we obtained a combination of 49.4% of 2- methylcyclohexanol and 50.6% 3-methylcyclohexanol. The 49.4% C-2 addition consisted of a combination of 14.6% the cis-2-methylcyclohexanol and 34.8% trans-2- methylhexanol. The 50.6% corresponding to boron addition at the C-1 position was found to be a combination of 25.6% cis-3-methylcyclohexanol and 25.0% trans-3- methylcyclohexanol.

Scheme 4.10

Borane•dimethylsulfide was the hydroborating agent selected for the research completed for 3-methylcyclohexene after taking into consideration the experimental advantages seen over other possibilities in the hydroboration of BH3/2-methyl-2-butene.

Smaller alkenes the hydroboration of methylcyclohexene has the advantage that lost of the product alcohol of the aqueous layer after oxidation is expected to be insignificant. This hydroboration could be performed using neat borane which allowed for direct

analysis of the reaction by 1H NMR of and an oxidized aliquot extracted with toluene d8 1_{H NMR signals observed for the carbonyl protons of the product’s cis-2-}

methylcyclohexanol and trans-2-methylhexanol was identified based on known spectra. A spectrum of a mixture of cis-3-methylcyclohexanol and trans-3-methylhexanol was also available. The 1H NMR peaks corresponding to the carbonyl protons of that spectra were compared to the findings of previous research on the conformational equilibria of trans-3-X-cyclohexanols,ref which provided detail NMR of trans-3-methylhexanol leading to the final identification.

Obtaining an accurate experimental selectivity for the hydroboration of 3- methylcyclochexene was not as straight forward as had been anticipated. As in the hydroboration of 2-methyl-2-butene we observe by 1H NMR that the reaction mixture was not a clean combination of the anticipated alcohols. Some of the impurities appeared to isomerization of the alkyl or dialkyl borane. This was concluded after analyzing the known 1H NMR some of the possible product isomers. All of the percentages of the products change significantly after a week as shown below. For a hydroboration of 3-methylcyclohexene with 100 equivalents of borane, that was left for over a week, the products ratio changed from 25.0% trans-3-methylcyclohexanol at short reaction times to 14.7% in the neat reaction, from 14.6% the cis-2- methylcyclohexanol when the reaction is pure to 6.3%, from 25.6% cis-3- methylcyclohexanol to 17.2%, and 34.8% trans-2-methylhexanol to 20.8%. The reaction in plain 100 equivalents of borane changed from a nearly equal mixture 2- methylcyclohexanol and 3-methylcyclohexanol at a short reaction time to a mixture of

27.1% 2-methylcyclohexanol, 31.9% 3-methylcyclohexanol, along with 41% of other alcohol and the reaction continued for over a week.

Another example isomerization was observed for the hydroboration of 3- methylcyclohexene with 0.3 equivalent of borane, and the reaction was left for over a two day period. The products ratio obtained was 12.2% trans-3-methylcyclohexanol, 3.1% cis-2-methylcyclohexanol, 26.0% cis-3-methylcyclohexanol (the integration to estimate this percentage combined the desired peak plus other impurities that could not be avoided), and 5.0% trans-2-methylhexanol. Therefore, in a 0.2 equivalents of borane reaction gives 49% of 2-methylcyclohexanol, but if the reaction mixture is left for a long period of time at 22 °C with excess alkene the mixture changes to 7.8% 2- methylcyclohexanol and a lot more impurities are observed (some identified as isomers). It is particular noticeable that the 2-methycyclohexanol dropped drastically in amount. It was observed that isomerization was unavoidable when an excess of alkene is added. For this reason, the reaction mixture could not be determined accurately when using small amounts of borane.

With experimental results in hand, we turned to evaluating the ability of transition state theory to predict the selectivity in this reaction. To determine the predictions of transition state theory a series of structures was located in gas phase calculations for integration of 3-methylcyclohexene with BH3, using B3LYP/6-31G*,

B3LYP/6-31+G** and B3LYP/CBSB7 (Figure 4.8). Single point energies with a variety of method/basis set were then obtained for each of these structures using the geometries obtained from B3LYP/6-31+G**. The methods/basis sets used for the single

point calculations of structures located for all transition sates, starting material and complexes were: CCSD(T)/6-311+G**, CCSD(T)/6-31+G**, CCSD(T)/aug-cc-pvdz, CCSD(T)/cc-pvdz, MO5/631+G**, MP4(sdq)/aug-cc-pvdz, MP4(sdtq)/cc-pvtz, B1B95/6-31+G**, MPWLYP/6-31+G**, MPWPW91/6-31+G**, TPSSTPSS/cc-pvtz, MO5/631+G**. In the case of G3B3 energy calculations, the geometries were calculated using B3LYP/6-31G*. The methods/basis sets used were chosen based on the margin of RMS error predicted for the previously discussed energy calculations for the hydroboration of propene with BH3. A summary of all the predicted enthalpies and free