Reduction of Cyclohexanones

Because of the number of conformations that need to be considered for acyclic systems, cyclohexanones are somewhat simpler for analysis. However, even for these systems the situation is not easily amenable to isolating specific components of selectivity. Several explanations have been proposed over the years to account for the preference of axial attack of cyclohexanones by sterically unhindered nucleophiles (L1A1H4, NaBH4, AIH3) [9]. Equatorial attack is favoured for sterically hindered cyclohexanones or reducing agents (Fig. 6-7). 

The first explanation for the preference for axial attack by hydride in conforma-tionally rigid sterically unhindered cyclohexanones became known as product development control and was suggested to reflect a late transition state [22]. For hindered ketones steric interference with the nucleophile was considered to favour equatorial attack and this became known as steric approach control caused by an early transition state. Hudec [23] proposed that the preferred direction of approach to a carbonyl group is controlled by deviations in the angle by which the axis of the 7i -orbital of the carbonyl carbon atom is twisted thereby making the faces of the carbonyl diastereotopic. 

The Felkin-Anh model has also been used to explain the preference for axial attack by nucleophiles on cyclohexanones and the effect of proximate substituents on facial selection. The anti periplanar geometry that Anh regarded as important in nucleophilic attack of carbonyl compounds is compromised by torsional strain in the reactions of cyclohexanones from the equatorial face. Felkin slated Whereas both torsional strain and steric strain can be simultaneously minimised in a reactant-like transition state when the substrate is acyclic... this is not possible in the cyclohexanone case.. ..These reactions all proceed via reactant-like transition states. In the absence of polar effects, their steric outcome is determined by the relative magnitude of torsional strain and steric strain [in the axial and equatorial transition states] [16]. 

Dannenberg [29] has attempted to provide a frontier orbital explanation for facial selectivity by a polarized n frontier orbital method. The new (polarized) orbitals are schematically represented as the combination of a p-orbital with two s-functions and have different coefficients associated with each face of each n center. 

The generally accepted order of increasing c-donor ability is ctco o cn o cci ctcc ctcH 7cs o csi. However, sulfur- and silicon-containing substituents are better able to stabilise an anti transition state than an antiperiplanar C-C or C-H bond. The Cieplak argument is supported by the stereochemistry of reduction of C3-substituted cyclohexanones. An electron-withdrawing group at C3 en- 

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Figure 8.11 Reduction of cyclohexanone with alcohol dehydrogenase and rhodium complex using electric power [7b].

Fukui [51] predicted the deformation of the LUMO of cyclohexanone by the orbital mixing rule [1,2] and explained the origin of the % facial selectivity of the reduction of cyclohexanone. Tomoda and Senju [52] calculated the LUMO densities on the... 

For reduction of monofunctional ketones, the most effective catalysts include diamine ligands. The diamine catalysts exhibit strong selectivity for carbonyl groups over carbon-carbon double and triple bonds. These catalysts have a preference for equatorial approach in the reduction of cyclohexanones and for steric approach control in the reduction of acyclic ketones.51... 

We recently reported that Cu/Si02 is an effective catalyst for the hydrogenation of cyclohexanones under very mild experimental conditions. Thus, a series of cyclohexanones with different substituents, including 3-oxo-steroids, could be reduced under 1 atm of H2 at 40-90°C, with excellent selectivity (5). The catalyst is non-toxic and reusable. This prompted us to investigate the reduction of cyclohexanones over a series of supported copper catalysts under hydrogen transfer (h.t.) conditions (2-propanol, N2, 83 °C) and to compare the results with those obtained under catalytic hydrogenation (n-heptane, 1 atm H2, 40-90°C) conditions. Here we report the results obtained in the hydrogenation of 4-tert-butyl-cyclohexanone, a molecule whose reduction,... 

Competitive reduction tests for cyclohexanone styrene, under transfer conditions, show preferential reduction of cyclohexanone however, under hydrogenation conditions the styrene is reduced exclusively.99 It is worth mentioning that the OsH2(r)2-H2)(CO)(P Pr3)2 precatalyst, formed by addition of NaBH4 to OsHCl (CO)(P Pr3)2, rapidly reduces phenylacetylene to styrene, under transfer conditions, but the reaction rate falls progressively due to the formation of Os(C=CPh)2 (CO)(P Pr3)2.72 As previously mentioned, an alkynyl-dihydrogen intermediate... 

Tributyltin hydride reduction of carbonyl compounds. The reduction of carbonyl compounds with metal hydrides can also proceed via an electron-transfer activation in analogy to the metal hydride insertion into TCNE.188 Such a notion is further supported by the following observations (a) the reaction rates are enhanced by light as well as heat 189 (b) the rate of the reduction depends strongly on the reduction potentials of ketones. For example, trifluoroacetophenone ( re<1 = —1.38 V versus SCE) is quantitatively reduced by Bu3SnH in propionitrile within 5 min, whereas the reduction of cyclohexanone (Erea — 2.4 V versus SCE) to cyclohexanol (under identical... 

Under certain conditions, the trifluoroacetic acid catalyzed reduction of ketones can result in reductive esterification to form the trifluoroacetate of the alcohol. These reactions are usually accompanied by the formation of side products, which can include the alcohol, alkenes resulting from dehydration, ethers, and methylene compounds from over-reduction.68,70,207,208,313,386 These mixtures may be converted into alcohol products if hydrolysis is employed as part of the reaction workup. An example is the reduction of cyclohexanone to cyclohexanol in 74% yield when treated with a two-fold excess of both trifluoroacetic acid and triethylsilane for 24 hours at 55° and followed by hydrolytic workup (Eq. 205).203... 

Pioneering studies on a different class of transfer hydrogenation catalysts were carried out by Henbest et al. in 1964 [15]. These authors reported the reduction of cyclohexanone (4) to cyclohexanol (5) in aqueous 2-propanol using chloroiridic acid (H2IrCl6) (6) as catalyst (Scheme 20.2). In the initial experiments, turnover frequencies (TOF) of 200 h 1 were reported. 

Using two types of specially synthesized rhodium-complexes (12a/12b), pyruvate is chemically hydrogenated to produce racemic lactate. Within the mixture, both a d- and L-specific lactate dehydrogenase (d-/l-LDH) are co-immobilized, which oxidize the lactate back to pyruvate while reducing NAD+ to NADH (Scheme 43.4). The reduced cofactor is then used by the producing enzyme (ADH from horse liver, HL-ADH), to reduce a ketone to an alcohol. Two examples have been examined. The first example is the reduction of cyclohexanone to cyclohexanol, which proceeded to 100% conversion after 8 days, resulting in total TONs (TTNs) of 1500 for the Rh-complexes 12 and 50 for NAD. The second example concerns the reduction of ( )-2-norbornanone to 72% endo-norbor-nanol (38% ee) and 28% exo-norbornanol (>99% ee), which was also completed in 8 days, and resulted in the same TTNs as for the first case. 

It is worth noting that finding a secondary a-deuterium KIE larger than the EIE is not unique. In fact, it has been found in several other reactions. For instance, Cleland and co-workers (Cook et al., 1980,1981 Cook and Cleland, 1981a,b) found unexpectedly large secondary a-deuterium KIEs in some enzymatic reactions for example, a secondary a-deuterium KIE of 1.22 for the reduction of acetone catalysed by yeast alcohol dehydrogenase and a KIE of 1.34 for the reduction of cyclohexanone catalysed by horse-liver dehydrogenase. 

The two-phase reduction of cyclohexanones by sodium dithionite in the presence of a stoichiometric amount of Adogen gave higher yields of the cyclohexanols than those obtained by the standard procedure using sodium dithionite in a water dioxane system (Table 11.9). A marked improvement in yield was also observed with the reduction of sterically hindered 2,6-dimethylcyclohexanone and there was a greater degree of stereoselectivity, which was comparable to that noted for the corresponding reduction with the borohydride ion [4]. 

Yeast alcohol dehydrogenase (YADH), catalysis of reduction by NADH of acetone formate dehydrogenase (FDH), oxidation by NAD of formate horse-liver alcohol dehydrogenase (HLAD), catalysis of reduction by NADH of cyclohexanone With label in NADH, the secondary KIE is 1.38 for reduction of acetone (YADH) with label in NAD, the secondary KIE is 1.22 for oxidation of formate (FDH) with label in NADH, the secondary KIE is 1.50 for reduction of cyclohexanone (HLAD). The exalted secondary isotope effects were suggested to originate in reaction-coordinate motion of the secondary center. 

Reduction of cyclohexanone oxime with lithium aluminum hydride in tetra-hydrofuran gave cyclohexylamine in 71% yield [809], and reduction of ketoximes with sodium in methanol and liquid ammonia [945] or in boiling ethanol [946] afforded alkyl amines, usually in good to high yields. Stannous chloride in hydrochloric acid at 60° reduced the dioxime of 9,10-phenanthra-... 

Preparative scale reduction of cyclohexanone affords principally the tail-to-tail hydrodimer 23 and some of the hcad-to-tail isomer 24 [93]. The proportions vary with pH, and no head-to-head pinacol has been isolated. Both meso- and ( )-forms... 

The axial equatorial isomer ratio for cyclohexanols obtained by reduction of cyclohexanones depends upon the solution pH (see Table 10.6). In alkaline or initially neutral but unbuffered solutions [59, 60], this ratio approaches the value at thermodynamic equilibrium The equatorial-aicohol, for exanq>le 9, is generated [61] from reduction of steroid ketones. In acid buffers, the thermodynamically less... 

You can also catalytically reduce aldehydes and ketones to produce 1° and 2° alcohols. Reduction conditions are very similar to those used to reduce alkene double bonds. If a molecule possesses both a double bond and an aldehyde or ketone functional group, reduction of the aldehyde or ketone group is best carried out using sodium borohydride. The reduction of cyclohexanone by hydrogen gas with a platinum catalyst produces cyclohexanol in good yield. 

The large steric requirement of L-Selectride generally favors reduction of cyclohexanones to form axial alcohols. However, in this cw-decalone example, the formation of the axial alcohol is hindered by the adjacent ring. 

The catalytic effect of DMP+ can be best demonstrated with an example. Consider the reduction of cyclohexanone 16). This substrate does not exhibit a polarographic wave, nor a CV reduction peak (Fig. la and 2a). On the other hand, DMP+ shows... 

Catalytic Oppenauer oxidations (Eq. 28) and Meerwein-Ponndorf-Verley reductions (Eq. 29) were studied in detail [232,234]. The gadolinium derivative, employed in situ without elimination of LiCl, was reported to be ten times more reactive in the MPV reduction of cyclohexanone as the standard reagent Al(OiPr)3 [235]. 

In non-hydroxylic solvents, the effects of the cation co-ordination become important, particularly if the cation is Li+ or Zn + 2. Lithium borohydride reductions of cyclohexanone, in THF, for example, are strongly inhibited by addition of the stoichiometric amount of the lithium specific [2.1.1]cryptand (Handel and Pierre, 1975). In the reduction of a,P-unsaturated ketones, lithium borohydride shows a strong selectivity for 1,2-addition (D Incan et al., 1982a,b) but in the presence of the cryptand, conjugate addition is favoured indeed, the selectivity is then indistinguishable from tetrabutyl-ammonium borohydride (D lncan and Loupy, 1981 Loupy and Seyden-Penne, 1979, 1980). 

In contrast, sterically undemanding hydride donors such as NaBH4 or LiAlH4 reduce 4-fert-butylcyclohexanone preferentially through an axial attack. This produces mainly the cyclohexanol with the equatorial OH group (Figure 8.8, middle and bottom reactions). This difference results from the fact that there is also a stereoelec-tronic effect which influences the diastereoselectivity of the reduction of cyclohexanones. 

A graduate student was studying enzymatic reductions of cyclohexanones when she encountered some interesting chemistry. When she used an enzyme and NADPH to reduce the following ketone, she was surprised to find that the product was optically active. She carefully repurified the product so that no enzyme, NADPH, or other contaminants were present. Still, the product was optically active. 

Propose a mechanism for both parts of the Wolff-Kishner reduction of cyclohexanone the formation of the hydrazone, then the base-catalyzed reduction with evolution of nitrogen gas. 

We discussed the reduction of cyclohexanones in Chapter 18 and established that reducing agents prefer the equatorial approach while small reagents may prefer to put the OH group in the more stable equatorial position. If the nucleophile is not H but something larger than OH then we can expect equatorial attack to dominate both because of ease of approach and because of product stability. 

Fig. 32 Reduction of cyclohexanone catalyzed by HLADH with simultaneous hydrogenase-driven regeneration of NADH in an organic-aqueous two-phase system...

Several organic solvents were investigated with regard to stability and activity of HLADH as well as their influence on the hydrogenase-driven reaction. Hydrophobic solvents such as heptane or toluene proved to be the most suitable solvents for the coupled enzyme-system. Furthermore, it became apparent that nonimmobilized cells, permeabilized with cetyl-trimethylammonium bromide, showed the best results for NADH regeneration. After optimization the conversion in heptane with 10% water yields 99% cyclohexanol by reduction of cyclohexanone. 

Especially worth mentioning in a green context is the use of mesoporous materials and zeolites, as stable and recyclable catalysts for MPV reductions. High activity was obtained by using zeolite-beta catalysts. Beta zeolites have a large pore three-dimensional structure with pores of size 7.6 x 6.4 A2 which makes them suitable for a large range of substrates. Al, Ti- and Sn-beta zeolite have all been used as catalysts for the selective reduction of cyclohexanones [40-42]. The... 

Cieplak ° countered the Anh explanation with an alternative orbital model. He noted that reductions of cyclohexanones and other additions at carbonyls occasionally resulted in the major product coming from the Eelkin-Anh minor TS. Arguing that since the incipient bond was electron deflcient—a partial bond lacks the full two-electron occupation—it is donation of density from the Oc2-l into the Oc-nuc oi ital that will stabilize the TS (Scheme 6.3). Support for the Cieplak model was provided by experimental results for nucleophilic addition to... 

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