Synthesis of cyclohexanol

Figure 3.3 shows a simple example of a retrosynthetic synthesis of cyclohexanol. Cyclohexanol may be disconnected to a hydride ion and a hydroxycarbocation (the synthons). Sodium borohydride and cyclohexanone are the synthetic equivalents of these two synthons. Thus, reacting cyclohexanone with NaBH will produce cyclohexanol. 

Oxidation of Cyclohexane. The synthesis of cyclohexanol and cyclohexanone is the first step in the transformation of cyclohexane to adipic acid, an important compound in the manufacture of fibers and plastics. Cyclohexane is oxidized industrially by air in the liquid phase to a mixture of cyclohexanol and cyclohexanone.866 872-877 Cobalt salts (naphthenate, oleate, stearate) produce mainly cyclohexanone at about 100°C and 10 atm. The conversion is limited to about 10% to avoid further oxidation by controlling the oxygen content of the reaction mixture. Combined yields of cyclohexanol and cyclohexanone are about 60-70%. 

Cyclohexane, the six-carbon ring hydrocarbon with the molecular formula C6H12, is the most significant of the cyclic alkanes. Under ambient conditions it is a clear, volatile, highly flammable liquid. It is manufactured by the hydrogenation of benzene and is used primarily as a raw material for the synthesis of cyclohexanol and cyclohexanone through a liquid-phase oxidation with air in the presence of a dissolved cobalt catalyst. 

Frank, S. Qi, Z. Sundmacher, K. Synthesis of cyclohexanol by three-phase reactive distillation influence of kinetics on phase equilibria. Chem. Eng. Sci. 2002, 57 (9), 1511-1520. 

Contrary to the hydroacylation of 4-pentenals, 6,7-unsaturated aldehydes are cyclized in an ene-type reaction to form cyclohexanols. Thus, ( + )-citronellal gives optically active cyclo-hexanol products using the same catalyst27, 59. This type of reaction can also be induced by acids and is frequently used in the stereoselective synthesis of cyclohexanol derivatives60-67,79. 

HLADH [19]. Figure 6 shows the mechanism for the synthesis of cyclohexanol coupled with the NADH regeneration. The HLADH converts cyclohexanone into the corresponding alcohol consuming NADH. To regenerate the cofactor, the oxidized form reacts with the reduced form of a mediator. The regenerated NADH is now... 

A synthetic equivalent is the reagent that is actually used as the source of a synthon. In the synthesis of cyclohexanol, cyclohexanone is the synthetic equivalent for the a-hydroxycarbocation, and sodium borohydride is the synthetic equivalent for hydride ion. Thus, cyclohexanol, the target molecule, can be prepared by treating cyclohexanone with sodium borohydride. 

Recognizing that cyclohexene may be prepared by dehydration of cyclohexanol a prac tical synthesis of cyclohexane from cyclohexanol becomes apparent... 

Cycloheptatrienes, synthesis of 801 Cyclohexadienes 800, 801 Cyclohexanols, synthesis of 838 Cyclopentanones, naturally occurring 321 Cyclopentanone sulphoxides, reactions of 341... 

Br(OAc)J Oxidations of Alcohols Investigated in Micro Reactors Organic synthesis 83 [OS 83] Br(OAc)J Oxidation of cyclohexanol... 

Figure 7.14 Biocatalytic and chemical synthesis of (I ff,2.S )-2-methy 1-1-cyclohexanol...

A" 0-Butenolide, 46, 22 /-Butyl alcohol, in synthesis of phenyl /-butyl ether, 45, 89 reaction with sodium cyanate and trifluoroacetic acid, 48, 32 /-Butyl azidoacctatc, 46, 47 hydrogenation of, 45, 47 /-Butyl carbamate, 48,32 /-Butyl chloroacetate, reaction with sodium azide, 45, 47 /ra S-4-/-BuTYI,CYCLOHEXANOL, 47,16... 

Other mediators which have been used in combination with diaphorase for the regeneration of NAD+ are riboflavin and Vitamin K3, which is 2,3-dimethyl-1,4-naphthoquinone. However, especially riboflavin is not stable enough for synthetic applications [40]. Better stability is exhibited by phenanthrolindiones as mediators. In combination with diaphorase, Ohshiro [41] showed the indirect electrochemical oxidation of cyclohexanol to cyclohexanone using the NAD+ dependent HLADH with a turnover frequency of two per hour. For an effective enzymatic synthesis, this turnover frequency, however, would be too small. In our own studies, we were able to accelerate the NAD(P)+ regeneration considerably by lowering the electron density within the... 

The same authors 83) used the chiral ketone (46) as substrate for the preparation of optically active cyclohexanol derivatives (47) which may be useful intermediates in the synthesis of chiral natural products, such as (—)-mesenbranoene, (+)-2-carene etc. 

The discovery of 1 -aryl-1 -dimethylamino-cyclohexanes resulted from a surrey of compounds in which aromatic and basic features, both critical structural requirements of opioid analgesics, but usually separated by two or three carbon atoms, are linked to the same quaternary carbon. The synthesis of these compounds yielded a series of highly potent opioids (e.g. 1-Benzyl-4-(4-bromo-phenyl)-4-dimethylamino-cyclohexanol), however none of them are in clinical use (Lednicer et al., 1981). 

Using air, the oxidation of hydrocarbons generally results in a mixture of oxygenated compounds and is not a useful synthesis of alcohols except under special circumstances. Cyclohexanol may be prepared by air oxidatron of cydohexane inasmuch as only one isomer can result. 

Homolytic liquid-phase processes are generally well suited to the synthesis of carboxylic acids, viz. acetic, benzoic or terephthalic acids which are resistant to further oxidation. These processes operate at high temperature (150-250°C) and generally use soluble cobalt or manganese salts as the main catalyst components. High conversions and selectivities are usually obtained with methyl-substituted aromatic hydrocarbons such as toluene and xylenes.95,96 The cobalt-catalyzed oxidation of cyclohexane by air to a cyclohexanol-cyclohexanone mixture is a very important industrial process since these products are intermediates in the manufacture of adipic acid (for nylon 6,6) and caprolactam (nylon 6). However, the conversion is limited to ca. 10% in order to prevent consecutive oxidations, with roughly 70% selectivity.97... 

Adipic acid is a most important petrochemical product which is mostly used for the synthesis of nylon 6.6 from its condensation with hexamethylenediamine. Cyclohexane is transformed to adipic acid in two steps (a) oxidation of cyclohexane to a cyclohexanol-cyclohexanone mixture (ol-one) via the formation of cyclohexyl hydroperoxide followed by (b) oxidation of the ol-one mixture to adipic acid by nitric acid (equation 239). 

The oxidation of cyclohexane to cyclohexanone and cyclohexanol is an important industrial procedure used in the synthesis of adipic acid. Srinivas and Mukhopadhyay (1994) reported the oxidation of cyclohexane in sc C02, yielding cyclohexanone and cyclohexanol as the major reaction products. At the high temperatures employed in this study (>137°C), cyclohexyl hydroperoxide (c-C6HnOOH), which is produced by the mechanism outlined in Scheme 4.11, decomposes to cyclohexanone and cyclohexanol. 

As another example of the systematic approach to multistep synthesis, let s consider the synthesis of l-bromo-2-methylcyclohexane from cyclohexanol. 

Propose a Williamson synthesis of 3-butoxy-l,l-dimethylcyclohexane from 3,3-dimethyl-cyclohexanol and butan-l-ol. 

A number of patents have been applied for the synthesis of cyclohexanone by hydrogenation of phenol where palladium catalysts have been employed.134 The presence of basic components such as CaO, MgO, and NajCOj has often been claimed to be effective for this purpose. As an example, 1000 parts of phenol was hydrogenated over 1 part of Pd-C containing 0.01 part of Na2C03 and 5000 ppm of Na in a 16.5% solution of aqueous ethanol at 186°C and 0.48 MPa H2 for 2.5 h to give a mixture of 97.2% of cyclohexanone, less than 0.5% of phenol, and cyclohexanol.134a In another patent, the reaction of 1 mol of phenol and 2 mol of cyclohexanol to give 3 mol of cyclohexanone was carried out over a palladium catalyst at 100-200°C (eq. 11.26).135... 

Addition of BuiSnLi to cyclohex-2-enone followed by enolate trapping with n-decyl iodide proceeded with high diastereoselectivity to provide the 2,3-rrdiR5-stannyl ketone (16), which could be equilibrated with the cis diastereomer (17) upon treatment with base. LAH reduction, followed by separation of the diasteteomers, afforded samples of the 2-alkyl-3-stannylcyclohexanols as shown in Scheme 17. Iodine(III)-mediated fragmentation was shown to proceed in a stereospecific anti manner, with either of the rrdiRr-2,3-cyclohexanols affording ( )-enal (18), and the cir-2,3-alcohol the (Z)-enal (19 Scheme 17). Enal (18) was then utilized in a stereoselective synthesis of the mosquito pheromone, erythro-6-asx-toxyhexadiecan-S-olide (20 Scheme 18). ... 

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