Menthol stereoisomers

Menthol is the isomer that occurs most widely in nature. It is the main component of peppermint and cornmint oils obtained from the Mentha piperita and Mentha arvensis species. Esterified menthol also occurs in these oils (e.g., as the acetate and iso valerate). Other menthol stereoisomers may be present in these oils as well. 

METHYLENE UNIT (MU) VALUES OF MENTHOL STEREOISOMERS MENTHOGLYCOL AND NEOMENTHOGLYCOL [35]... 

Chiral Ni-Co catalysts were examined in an industrially important reaction, in the hydrogenation of the equilibrated mixture of menthone and isomenthone (70 30) into menthol stereoisomers. The use of the Ni-Co-(90 10)-TA catalyst resulted in an optical yield of 54% (Klabunovskii et al. ). On an RCo-TA catalyst the unavailable neoisomenthol was obtained with a yield of 80% (Zubareva et al. ). 

Figure6.17.12 Calculated concentration profiles of the menthol stereoisomers inside the catalyst particles (200°C, 7.5 MPa H2) at three different modified residence times. The gray symbols represent three reference values as also indicated in Figure 6.17.11. Adapted from Etzold and Jess (2008).

Etzold, B. and Jess, A. (2008) Heterogeneously catalysed epimerisation of menthol stereoisomers - an instructive example to account for diffusion limitations in complex reaction networks. Chem. Eng. Techn., 31,1282-1289. 

Schlemenat, A., Langer, R Dreisbach, C Gross, H.-J., Prinz, T, Schulze-Tilling, A., Friederich, M Jentsch, J.D., and John, G. (2001) Isomerization process and supported mihenium catalysts for the preparation of D, L-menthol from menthol stereoisomers. DE10023283. 

In Problem 4 25 you were asked to draw the preferred conformation of menthol on the basis of the information that menthol is the most stable stereoisomer of 2 isopropyl 5 methylcyclo hexanol We can now completely descnbe (—) menthol structurally by noting that it has the R con figuration at the hydroxyl substituted carbon... 

Another large volume monoterpene is (—)-menthol, a compound that belongs to a family of eight stereoisomers. Only (—)-menthol (1 R,2S,3R-configuration) possesses the characteristic peppermint odor and exerts the unique cooling sensation on the skin. Most (—)-menthol is obtained by freezing peppermint or cornmint oil, followed by recrystallization. Besides this natural menthol some 20% or 3000 t a-1 is made by (semi)-synthesis. 

The synthetic process starts with the isopropylation of m-cresol to yield thymol. After catalytic hydrogenation a mixture of stereoisomers is obtained from which (+)-menthol is isolated. The process requires much separation and recycling work. In contrast, the semi-synthetic process of Takasago (Scheme 5.5) leads essentially to stereopure (—)-menthol [19]. 

The enantiomeric menthols have identical physical properties (apart from their specific rotation), but the racemates differ from the optically active forms in, for example, their melting points. Although the differences between the boiling points of the stereoisomers are small, the racemates can be separated by fractional distillation. Boiling points (in °C at 101.3 kPa) are as follows ... 

Isopulegol can be isolated from this mixture and hydrogenated to (-)-menthol. The remaining isopulegol stereoisomers can be partly reconverted into (+)-citronellal by pyrolytic cleavage and reused in the cyclization procedure [79]. 

However, the isopulegol mixture can also be hydrogenated to produce a mixture of menthols the individual stereoisomers are then separated by distillation. To obtain optically pure (-)-menthol, a resolution step involving a suitable crystalline derivative (such as the benzoate) is required. The undesired stereoisomeric menthols mainly (+)-neomenthol and (+)-isomenthol, are epimerized to an equilibrium mixture (e.g., by heating in the presence of sodium menthylate). (-)-Menthol is then again separated from the mixture. 

CioHigO, Mr 154.25, pure (-)-isopulegol [89-79-2], Z>/>ikPa 74 °C, df 0.9062, 1.4690, [q ]d - 23.6°. Like menthol, isopulegol has three asymmetric carbon atoms and, therefore, four stereoisomers, each occurring as a pair of optically active antipodes. 

The only chiral compounds are (e) menthol which has 2 = 8 stereoisomers, (h) halothane which has 2 = 2 stereoisomers, and (k) thyroxine which has 2 =2 stereoisomers. 

In other systems, a particular structure may be found as a mixture of diastereoisomers. Peppermint (Mentha x piperita Labiatae/Lamiaceae) typically produces (—)-menthol, with smaller amounts of the stereoisomers (+)-neomenthol, (+)-isomenthol, and (+)-neoisomenthol, covering four of the possible eight stereoisomers (Figure 5.16). Oils from various Mentha species also contain significant amounts of ketones, e.g. (—)-menthone, (+)-isomenthone, (—)-piperitone, or (+)-pulegone. The metabolic relationship of... 

Because menthol is the most stable stereoisomer of this constitution, all three of its substituents must be equatorial. We therefore draw the chair form of the preceding structure, which has the hydroxyl group equatorial and up, placing isopropyl and methyl groups so as to preserve the R configuration at C-l. 

There are four diastereomeric menthols according to the relative orientations of the methyl, isopropyl, and hydroxyl groups. They are known as menthol, isomenthol, neomenthol, and neoisomenthol, each of which exists in two enantiomeric forms. The most abundant and readily available is /-menthol, or (/A 2.S, 5iZ)-(-)-menthol (23), whereas other stereoisomers, although available from nature, are more economically produced through chemical derivatizations from menthone, limonene, and a-pinene. Commercial (-)-menthol from natural sources can be as pure as 99% in both chemical and optical purities. Synthetic menthol is currently made by an asymmetric isomerization (see Chapters 12 and 31).34... 

Draw both chair conformations for menthol (a component of peppermint oil) and its stereoisomer, neomenthol. Which groups are axial and which groups are equatorial Explain which conformation is more stable for each stereoisomer. Which stereoisomer is more stable By how much energy ... 

Other workers [35] have described several methods for the silylation of different stereoisomers of menthol and separated them on a column coated with SE-30. They recommend n-butyl boronates for the GC analysis of menthoglycol and neomentho-glycol and HFB esters for sensitive analysis at the nanogram level. Retention data for some derivatives of these substances are listed in Table 5.3. 

Disposition in the Body. Menthol is excreted in the bile and urine as a glucuronide conjugate the various stereoisomers differ quantitatively in the extent to which they conjugate with glucuronic acid. Menthol may occur in the conjugated form as a metabolite of pulagone which is a constituent of pulegium oil. 

Menthone can exist in two diastereomeric forms cis- and trans- known as isomenthone and menthone respectively. Both of these forms are chiral and can be found in two enantiomeric forms (+) and (-). When menthone is reduced to secondary alcohol - menthol, the new asymmetry centre appears and menthol with three asymmetric carbon atoms can be found in eight optically active forms. Thus in the group of eight stereoisomers of... 

Menthanes, which include menthol, menthonc, terpineol, and carvone, are some of the best known monoterpene-based chiral synthons in organic synthesis. They are all relatively inexpensive and are commercially available in bulk quantities. Menthols and their corresponding ketones, menthones. were first isolated from peppermint oils of various species of Mentha piperita L [30]. Menthones can exist in two diastereomeric forms, each with two enantiomers. The ones with the methyl and isopropyl groups in a Zrans-orientation are termed menthones, whereas those with the two in a cz.s-orientation are isomenthones. /-Menthone (22), also denoted as (7A,4S)-(-)-menthone. is the most abundant stereoisomer and is obtained by the dry distillation of the wood of Finns palustris Me II [31]. It can also be produced chemically by chromic acid oxidation of /-menthol (23) [32]. /-Menthone is commercially available in bulk quantities with optical purities of 90-98% ee [33]. 

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