3-Methylcyclohexanone

Treon JF, Crutchfield WE Jr, Kitzmiller KV The physiological response of rahhits to cyclohexane, methylcyclohexane, and certain derivatives of these compounds. I. Oral administration and cutaneous application. J Ind Hyg ToW 25 199-214, 1943 

Physical Form. Clear to pale yellow liquid 

Toxicology. In animals o-methylcyclohexa-none is an irritant of the eyes and mucous membranes, and at high concentrations it causes narcosis it is expected that severe exposure would produce the same effects in humans. 

Several species of animals exposed to 3500 ppm suffered marked irritation of the mucous membranes and became incoordinated after 15 minutes of exposure and prostrate after 30 minutes. Conjunctival irritation, lacrimation, salivation, and lethargy were observed in rabbits exposed to 1822 ppm 6 hours/day for 3 weeks. Exposure of mice to 450 ppm for an unspecified time period resulted in severe irritation of the eyes and respiratory tract.  

Repeated cutaneous application to rabbits of large doses of the liquid caused irritation of the skin, tremor, narcosis, and death the minimum lethal dose was between 4.9 and 7.2 g/k.  

---

Methylcyclohexanone is reduced to give 65 % of the tmns-2L cdho. However, the larger reagents, disiamylborane and diisopinocamphenylborane, give respectively 77 % and over 90 % of the cw-alcohol. Later work confirmed that reductions of 2-alkylcycloalkanones with dialkyl boranes give predominantly the less stable alcohol/ ... 

The pyrrolidine enamine of 2-methylcyclohexanone (7) was in fact found to be quite inert toward further alkylation and was shown to consist only of the trisubstituted isomer (4) on the basis of the NMR spectral data. The... 

The presence of 1,3-diaxial interaction between the C-2 alkyl group and the C-4 axial hydrogen atom is reflected in the rate of enamine formation of 2-substituted cyclohexanone. It has been shown by Hunig and Salzwedel (20) that even under forcing conditions, the yield of pyrrolidine and morpholine enamines of 2-methylcyclohexanone does not exceed 58%, whereas the C-2 unsubstituted ketones underwent enamine formation under rather milder conditions in better than 80 % yield. 

Although the enamine (30) underwent addition reaction with ethyl azido-dicarboxylate, it failed to add another mole of jS-nitrostyrene. In a similar manner the morpholine enamine of 2-methylcyclohexanone also failed to react with this olefin, i.e., jS-nitrostyrene, which is undoubtedly due to the 1,3-diaxial interaction between the methyl group and the incoming electrophile in the transition state. 

The magnitude of the preference for the formation of the less substituted enamine from unsymmetrical ketones as expressed by the general rule given above is not entirely clear. House and Schellenbaum 48) have reported that 2-methylcyclohexanone and pyrrolidine produce a product mixture of tetra- and trisubstituted enamines in a ratio of 15 85. The estimate of this ratio was made from NMR data. In contrast Stork and co-workers (9) report the formation of 100% trisubstituted enamine as determined by NMR spectroscopy. 

The reactions of pyrrolidinocyelohexenes with acid have also been Considered from a stereochemical point of view. Deuteration of the 2-methylcyclohexanone enamine gave di-2-deuterio-6-methylcyclohexanone under conditions where ds-4-/-butyI-6-methyIpyrrolidinocycIohexene was not deuterated (2J4). This experiment supported the postulate of Williamson (2JS), which called for the axial attack of an electrophile and axial orientation of the 6 substituent on an aminocyclohexene in the transition state of such enamine reactions. These geometric requirements explain the more difficult alkylation of a cyclohexanone enamine on carbon 2, when it is substituted at the 6 position, as compared with the unsubstituted case. 

The illumination of enamines as general activa ting derivatives of ketones in alkylation reactions also threw light on their special usefulness for controlling alkylations (3), particularly in the formation of monosubstituted cyclohexanones. Thus 2-methylcyclohexanone could be obtained in 80% yield from the pyrrolidine enamine of cyclohexanone, and further alkylation, which required more drastic conditions, gave only 2,6-dimethylcyclo-hexanone (1,237). 

The presence of an substituent, found in the pyrrolidine enamine of 2-methylcyclohexanone, blocks the possibility of an intramolecular proton transfer in the zwitterionic intermediate and thus only the benzocyclobutane... 

Methylcyclohexanone, pK 20, is typical of a weak acid that undergo H/D exchange. Identify the acidic protons of 2-methylcyclohexanone, i.e., those most susceptible to attack by base, as positions for which the value of the lowest-unoccupied molecular orbital (LUMO) is large. Use a LUMO map (the value of the LUMO mapped onto the electron density surface). Does this analysis correctly anticipate which of the anions obtained by deprotonation of 2-methylcyclohexanone is actually most stable Are any of the other ions of comparable stability, or are they aU much less stable ... 

LUMO map for 2-methylcyclohexanone reveals (in blue) acidic protons, susceptible to H/D exchange. 

Since most often the selective formation of just one stereoisomer is desired, it is of great importance to develop highly selective methods. For example the second step, the aldol reaction, can be carried out in the presence of a chiral auxiliary—e.g. a chiral base—to yield a product with high enantiomeric excess. This has been demonstrated for example for the reaction of 2-methylcyclopenta-1,3-dione with methyl vinyl ketone in the presence of a chiral amine or a-amino acid. By using either enantiomer of the amino acid proline—i.e. (S)-(-)-proline or (/ )-(+)-proline—as chiral auxiliary, either enantiomer of the annulation product 7a-methyl-5,6,7,7a-tetrahydroindan-l,5-dione could be obtained with high enantiomeric excess. a-Substituted ketones, e.g. 2-methylcyclohexanone 9, usually add with the higher substituted a-carbon to the Michael acceptor ... 

This procedure appears to be general and has been successfully applied to the following examples ethyl acetoacetate from acetone (68 %) ethyl benzoylacetate from acetophenone (74%) ethyl a-propionylpropionate from diethyl ketone (81%) ethyl 2-methylcyclohexanone-6-carboxylate from 2-methylcyclohexanone (67%). 

Sodium hydride, 50% dispersion in mineral oil Alpha Inorganics 2-Carbethoxycyclooctanone (Chapter 10, Section I) 2-Methylcyclohexanone A, EK Methyl vinyl ketone MCB, A... 

The situation is different for 2-methylcyclohexanone. 2-Methylcvclo-bexanone has no symmetry plane and is chiral because C2 is bonded to four different groups a -CH3 group, an —H atom, a -COCH2- ring bond (C1), and a —CH2CH2— ring bond (C3). 

Problem 19.4 How would you carry out the following reactions More than one step may be required, (a) 3-Hexvne 3-Hexanone, (b) Benzene —> m-Bromoacetophenone I (c) Bromobenzene —> Acetophenone (d) 1-Methylcyclohexene — 2-Methylcyclohexanone... 

Note in the ketone example that alkylation of 2-methylcyclohexanone leads to a mixture of products because both possible enolate ions are formed. In general, the major product in such cases occurs by alkylation at the less hindered, more accessible position. Thus, alkylation of 2-niethvTcyclohexanone occurs primarily at C6 (secondary) rather than C2 (tertiary). 

When optically active (fl)-2-methylcyclohexanone is treated with either aqueous base or acid, racemization occurs. Explain. 

---