Proposal for a New Total Synthesis of levo-Menthol

 

 

A proposed new multi-stage synthesis of l-()-menthol is discussed in this web page :

While menthol is a relatively simple molecule , the total synthesis of the levo enantiomer from common organic reagents is a surprisingly challenging project . The combination of simplicity of structure and a synthesis route involving several classic organic reactions [the references are presented at the end of the text , below] will make this study of particular interest to undergraduate organic chemistry students .

The regio- and stereochemistry of the intermediates and product are first established in the Diels-Alder cyclization reaction used for the skeletal formation . Further stereoselectivity is controlled in the hydroboration of the 5-acetoxy-limonene intermediate to menthyl acetate . Enantioselectivity may be at least partially accomplished during the Diels-Alder step by the use of a catalyst comprised of an electrophilic aluminum cation coordinated by chiral ligands .

 

Introduction

 

Menthol holds a prominent position in the flavoring and fragrances chemical specialties market . It's a familiar additive in many commercial products such as chewing gum , toothpaste , skin care products , medicines , candies , and cigarettes . Menthol is usually obtained from two principal sources : the natural product , from mint (a very common plant , found in temperate and tropical regions , from which spearmint and peppermint oils are extracted) ; and the industrial product , which is manufactured from a variety of simpler bulk chemicals , including petrochemicals and other precursors such as the b-pinene component of turpentine [underlined blue hyperlinks can be clicked when online to retrieve the article cited . The requested document will open in a new window] .

There is certainly no need for another commercial synthesis of menthol . Yet there is still an intellectual challenge , especially for “student organic chemists”, to study a highly specific new route to menthol . It's deceptively simple in chemical composition : 2-isopropyl-5-methyl-cyclohexanol . The natural product has a well-defined stereochemistry , and consists of the single mirror image molecule – enantiomer – levorotary (1R,2S,5R)-(–)-menthol , which produces the familiar cooling sensation in the human nose . The dextrorotary (1S,2R,5S)-(+)- enantiomer has a somewhat different smell and produces a lesser cooling sensation than the levo form . Industrial racemic menthol , comprised of 50% of each enantiomer , still has a pronounced “menthol smell” and is often suitable for many commercial applications .

To make things even more interesting , there are four stereoisomers of 2-isopropyl-5-methyl-cyclohexanol : menthol itself , isomenthol , neomenthol , and neoisomenthol :

The natural product from the mint plant is the single , specific molecule , levo-(–)-menthol :

Levo-menthol has the most pronounced fragrance and flavoring properties , is the most in demand , and is more expensive than racemic menthol . However , industrial chemical manufacturing processes invariably generate racemic mixtures of the four stereoisomers . For example , hydrogenation of thymol (2-isopropyl-5-methyl-phenol) over a Raney cobalt catalyst provides a high yield of the racemic stereoisomers , most of which – about 85% – consists of isomenthol .

Designing a synthesis route to the specific l-(–)-menthol enantiomer turns out to be more challenging than originally anticipated ! The objective of this essay is to outline a multi-stage total synthesis of levo-menthol , identical to the natural product from mint . The proposed synthesis will be regioselective : that is , the hydroxyl , isopropyl , and methyl groups will be located at the correct positions on the cyclohexane ring ; it will be stereoselective , in that those three substituents will have the correct spatial configurations relative to each other ; and possible methods for inducing a certain amount of optical activity in the product will be discussed , although asymmetric organic synthesis is still as much of an art as a science at this time . Hopefully the proposed route to menthol will be enantioselective to a certain extent for the desired levo isomer as well .

 

An Industrial Synthesis of Racemic and l-(–)-Menthol

 

Before embarking on a survey of the proposed new scheme , it might be interesting to briefly review an industrial process in which racemic and l-(–)-menthol are produced on a relatively large scale . The following synthesis route is described in an article in Chemical Engineering magazine and in a web page :

This sketch was copied (with minor annotations) from the web page , Menthol – A Cool Place , page 9 , “(–)-Menthol Synthesis from m-Cresol / Thymol”, Leffingwell & Associates . My thanks to the copyright owner .

First , the meta-cresol [3-methyl-phenol] feedstock was alkylated ortho to the hydroxyl to produce thymol [2-isopropyl-5-methyl-phenol] . Propylene gas was the alkylating agent , with the reaction carried out over an aluminum alkoxide heterogeneous catalyst . In an earlier (1939) Friedel-Crafts reaction propylene was condensed with m-cresol , using hydrofluoric acid as the catalyst , to produce a monoalkylated product (m.p. 43 C ; pure thymol melts at 51 C) . We may infer from this lowered melting point that a mixture of alkylated products was formed with the HF catalyst . Use of the aluminum alkoxide catalyst apparently resulted in the single desired thymol product . The aluminum cation may have coordinated to the cresol hydroxyl , then further coordinated to the propylene alkylating agent , leading to a regioselective propylation of the cresol :

In the second step , the thymol is hydrogenated to a mixture of the menthol stereoisomers . As mentioned above , thymol has been hydrogenated to the corresponding cyclohexanol with Raney cobalt catalyst , although the main isomer produced (about 85%) was isomenthol .

The key step in this industrial process is undoubtedly the third one , in which the mixture of menthol stereoisomers is catalytically “cracked”, or rearranged , into mostly racemic menthol . This impure menthol , produced in about 50% yield after the rearrangement reaction , is separated from the unwanted stereoisomers (which are recycled to the cracker unit) by fractional distillation . Industrial-scale spinning band distillation columns are now widely used in the production of very pure organic chemicals ; they are especially valuable in the fractionation of high-boiling oils in a vacuum or inert atmosphere .

The success of the catalytic cracking step derives from the relative thermodynamic stability of menthol compared to the neo- , iso , and neoisomenthol stereoisomers . Only in menthol are all three substituents on the cyclohexane ring in the energetically more favorable equatorial configuration :

Presumably in the cracking reaction the molecules are temporarily split open ; as they exit the reaction zone they recombine mostly into the more structurally stable menthol stereoisomer .

The fourth step in the Haarmann-Reimer process is the transesterification of the racemic menthol with methyl benzoate to produce racemic menthyl benzoate :

()-menthol + methyl benzoate ------ [acid catalyst] -------> ()-menthyl benzoate + methanol

Seeding of the racemic menthyl benzoate with seed crystals of the (–)-enantiomer causes the desired product , l-(–)-menthyl benzoate , to selectively crystallize from solution . It's collected and hydrolysed or saponified to l-(–)-menthol and benzoic acid . The latter by-product and the unwanted d-(+)-menthyl benzoate are recycled back into the process for re-use . The Leffingwell web page describing the Haarmann-Reimer process states that it's remarkably efficient in materials , with a 90+% overall process yield of l-(–)-menthol .

The two products from this synthesis route are racemic menthol , which is satisfactory for many applications , and the costlier l-(–)-menthol , which is preferred by some customers . This industrial manufacture of l-(–)-menthol is quite straightforward , if rather unsophisticated . It's more noteworthy for its creative chemical engineering than for its mundane organic chemistry . In particular it's deficient in stereoselectivity and entirely lacking in any sort of enantioselectivity (there is some regioselectivity in the thymol synthesis , as pointed out) . Nevertheless , it succeeds admirably in producing a high yield and moderate tonnage of very pure , pharmaceutical grade racemic menthol and its levo enantiomer .

Given the success of this and other industrial processes for the manufacture of menthol from petrochemicals and turpentine , why should we design yet another synthesis of it ? My objective in offering the following menthol synthesis is more “academic” than industrial . It's really intended for students of organic chemistry , to study , discuss, and possibly even to attempt as a research project (at least , for the more advanced undergraduates) . The chemistry and the molecules involved are fairly simple and are readily understood , and the synthesis scheme will hopefully be both mentally stimulating and educational .

 

A Proposed New Highly Selective Synthesis of l-(–)-Menthol

 

The following route is based on the synthesis of racemic limonene (“dipentene”) , described by Vig and coworkers :

The Diels-Alder reaction is a critical step in this menthol synthesis because it will produce a cyclohexane ring with regioselective and stereoselective control of the substituents (not illustrated in this particular dipentene case) . In Vig’s dipentene the methyl and isopropenyl groups were located on the 1,4 positions of the ring , respectively , as in menthol . Additional functionality will be required in our precursor dienophile , replacing methyl vinyl ketone , to install an an acetate group on limonene's carbon 5 in the new 5-acetoxy-limonene intermediate .

Our menthol synthesis will also require a stereoselective hydrogenation of the two olefin bonds . This might be accomplished by a hydroboration technique , which can be quite stereospecific in nature .

The overall proposed route to l-(–)-menthol is summarized in the following scheme :

Step 1 : Preparation of 3-keto-1-butenyl-1-acetate , CH3–CO–CH=CH–OAc .

The dienophile we require , replacing Vig’s methyl vinyl ketone , will be similar to it but with the addition of an acetate group on C1 , which will become C5 in the cyclohexene ring 2 formed in the Diels-Alder reaction . The target dienophile will then be CH3–CO–CH=CH–OAc , 3-keto-1-butenyl-1-acetate (or 1-acetoxy-1-buten-3-one or 2-acetyl-vinyl acetate) .

Before starting any organic synthesis project the researcher should , of course , conduct a thorough literature survey for published reports describing the preparation of any planned intermediates that aren't commercially offered . Unfortunately , the two prime search sources used by chemists , the hardcopy Chemical Abstracts and the electronic SciFinder Scholar , are no longer available to me . Preparation of the first intermediate in this menthol synthesis , 3-keto-1-butenyl-1-acetate , might have already been reported in the chemical literature , but I'm unaware of it , so I've suggested a possible route to it here .

The Darzens synthesis of unsaturated ketones (1910) is the aliphatic analogue of the more familiar Friedel-Crafts acylation of aromatic compounds . An acid chloride is added across an olefinic bond to create a b-chloroketone , which can often be isolated as a reasonably stable compound . The chloroketone can also be dehydrohalogenated to the corresponding unsaturated ketone (enone) .

I personally carried out a Darzens synthesis during the summer of 1969 , when I condensed ethylene gas with propionyl chloride in the presence of anhydrous AlCl3 as the Lewis acid catalyst for the reaction :

CH3CH2-CO-Cl + CH2=CH2 (g) ------- [AlCl3 , anhydrous] -------> CH3CH2-CO-CH2CH2-Cl

This synthesis of 1-chloro-3-pentanone had been studied forty years earlier by German chemists :

The Darzens acylation of vinyl acetate by acetyl chloride might be investigated. Vinyl acetate is an inexpensive industrial chemical and is used on a large scale in the manufacture of soft , flexible plastic materials and consumer goods . Because it can rapidly polymerize , especially in the presence of a cationic catalyst such as a Lewis acid , it would be advisable to :

* use a mild Lewis acid catalyst such as anhydrous zinc chloride or tin(IV) chloride , rather than a more powerful one like anhydrous AlCl3 or FeCl3 ;

* add the vinyl acetate to the acetyl chloride/catalyst mixture , slowly and dropwise , so that it never accumulates to any significant extent in the reaction flask , and so can't polymerize ; and ,

* additionally , an inert solvent such as carbon disulfide (often used with AlCl3 in conventional Friedel-Crafts acylations and alkylations) can futher dilute the sensitive vinyl acetate .

Acetic anhydride has been utilized in the Darzens acylation of olefins such as cyclohexene . A similar acylation procedure might be tried with vinyl acetate :

Note that in the acetic anhydride acylations an unstable aldol acetate (or 1,1-gem-diacetate , with vinyl acetate) is produced as the initial adduct ; it decomposes in situ to the enone and acetic acid . In the Darzens syntheses of enones with acid chlorides the intermediate chloroketones will sometimes spontaneously dehydrohalogenate to the enones in the reaction mixture , or during subsequent heating at one atmosphere pressure . They can also be dehydrohalogenated by suitable basic reagents such as tertiary amines (triethylamine , pyridine , etc.) . I suspect that in the vinyl acetate case the intermediate compound , 1-chloro-3-keto-butyl acetate , will be quite unstable because of the two electron-withdrawing substuents , Cl and OAc , on C1 . It will likely spontaneously dehydrohalogenate to the enone in the reaction mixture .

Enterprising student researchers might even try to carry out a Darzens acylation of acetylene gas with acetic anhydride to synthesize 3-keto-1-butenyl-1-acetate directly . In this case no acetic acid would be expelled as a by-product .

If successfully synthesized , the 3-keto-1-butenyl-1-acetate should be carefully purified and fully characterized (eg. GC , IR , UV/VIS , NMR , mass spectrum if available) . In particular , the researcher should ensure that the product has the correct trans (E) stereochemistry , as this will be essential in setting the proper trans configuration of the acetyl and acetate groups in the subsequent Diels-Alder cyclohexene intermediate 2 . The splitting patterns obtained in both H1 and C13 NMR analyses can help to confirm the cis/trans geometry of olefins .

 

Step 2 : Diels-Alder reaction of 3-keto-1-butenyl-1-acetate and isoprene .

This is probably the key step in the synthesis scheme , since most of the menthol carbon skeleton will be assembled in Step 2 . The Diels-Alder reaction is known to be highly stereoselective , and it can be quite regioselective too , as we'll see . The trans geometry of the acetyl and acetate groups should be retained after the enol acetate is combined with isoprene in the cyclization reaction . This is essential because the acetate and isopropyl substitiuents have a trans configuration in menthol . Stereochemical retention in the Diels-Alder reaction is demonstrated by the addition of maleic acid (cis , Z) and its geometrical isomer fumaric acid (trans , E) with anthracene . The cis and trans geometries of the carboxylic acid groups are retained in the products :

The Diels-Alder reaction can be highly regioselective . Dienes substituted on C2 generally provide “para” products with monosubstituted olefins , while those substituted on C1 produce “ortho” cyclohexane derivatives with CH2=CH–X dienophiles . Use of catalysts to speed up the reaction at ambient temperature can also dramatically influence the para-to-ortho ratio , as illustrated below :

Clearly , a catalyst should be used in the proposed Diels-Alder reaction of 3-keto-1-butenyl-1-acetate with isoprene :

* First , it will strongly favor the formation of the “para” isomer , which is what we want .

* Second , it will speed up the reaction ; it will permit milder (possibly ambient) reaction conditions to be used ; and it should result in a “cleaner” reaction with a purer product in a higher yield than without a catalyst .

* Third , if an asymmetric catalyst is used , it might induce asymmetry in the product . As we are aiming toward the synthesis of the specific l-(–)-menthol enantiomer , we should be alert to the possibility of inducing asymmetry in one or other of the intermediates in order to achieve this objective . This should preferably be accomplished in the first step in which one or more asymmetric centers are generated in the product . In the above synthesis scheme that would be intermediate 2 , 1-methyl-[E-(4-acetyl-5-acetoxy)]-cyclohex-D1,2-ene .

Aluminum chloride (and the SnCl4 used in the para-to-ortho example sketched above) , and Friedel-Crafts catalysts in general , are known to accelerate many Diels-Alder reactions . Nafion H , a fluorinated sulfonic acid polymer , will also catalyse the cyclization reaction , as will the Wurster Blue salt , tris(4-bromophenyl) aminium hexafluoroantimonate , which is a resonance-stabilized radical cation . Indeed , all of these Diels-Alder catalysts must function as electrophilic reagents , creating a cationic complex with the dienophile , making it more electrophilic toward the nucleophilic diene . Without such catalysts , the Diels-Alder reaction will succeed only when an electron-withdrawing group is attached to the olefin bond of the dienophile , in effect polarizing it and making it electrophilic to a certain extent .

Aluminum(III) has been incorporated into a coordinate covalent complex with another optically-active ligand , 1,2-diphenylethylene diamine , as the asymmetry-inducing reagent , diazaaluminolidine :

Several catalysts have been devised , including diazaaluminolidine above , that are remarkably effective in inducing asymmetry in organic reactions . In many cases nearly quantitative optical yields (enantiomeric excesses) of a specific enantiomer were obtained in the syntheses . That is , the product consisted almost entirely of one desired enantiomer , with little if any of the other one present . Unfortunately , there doesn’t seem to be any established repertoire of asymmetric induction catalysts for various transformations of interest . The researcher is thus obliged to devise such catalysts on a case-by-case basis , as must be done in this Diels-Alder step .

Diazaaluminolidine has been successfully used as an asymmetry-inducing catalyst in Diels-Alder cyclizations . It might very well be highly effective in the proposed reaction of 3-keto-1-butenyl-1-acetate with isoprene . However it's a rather sophisticated compound to prepare , and undoubtedly is very expensive . For an undergraduate organic chemistry project it might be preferable to examine an alternate asymmetry-inducing catalyst for the Diels-Alder step .

An interesting enantioselective catalyst has been used in the preparation of optically active polybenzofuran . The amino acid S-(–)-phenylalanine ,

was combined with anhydrous aluminum chloride in toluene at room temperature to form an AlCl3 : phenylalanine (~ 3 : 1) coordinate covalent complex as a clear , yellow-green solution . Although we would expect coordination of Al3+ to reduce its catalytic potency , this amino acid-based complex induced the polymerization (which likely has a free-radical mechanism) of benzofuran at –75 C . It also induced asymmetry in the resulting polybenzofuran .

This simple , inexpensive chiral catalyst , (AlCl3)3-S-(–)-phenylalanine , might be worthwhile investigating in the Diels-Alder step of the menthol synthesis . If the wrong configuration is induced in product 2 , the same complex could be tried again , but with R-(+)-phenylalanine as the amino acid ligand . Both forms of phenylalanine are commercially available , eg. from the Aldrich Chemical Company . The S enantiomer is the “natural” one , widespread in Nature in proteins , while the R enantiomer is the rarer “unnatural” form , and is derived from the resolution of racemic phenylalanine from chemists’ reaction flasks , rather than from Nature .

Pure enantiomers of other amino acids , and of tartaric acid , are also commercially available at a moderate cost , and might form useful catalytic complexes with aluminum chloride and other Friedel-Crafts catalysts . Alkaloids such as l-(–)-quinine and l-(–)-brucine could be tried as a ligand ; and the very common and cheap sugars a-D-(+)-glucose and (+)-sucrose (ordinary table sugar) might form chiral catalytic complexes with aluminum chloride and other electrophilic metal halides . Keep in mind that the spent catalyst must be cleanly separated from the product at the end of the reaction .

Step 3 : Wittig reaction to prepare 5-acetoxy-limonene , 3 .

As in Vig’s synthesis of dipentene , the acetyl group attached to the cyclohexene ring will be converted into the isopropenyl group by condensing it with the phosphorus ylid , Ph3P+–CH2- , in the Wittig olefination reaction . As an electron-withdrawing function the acetyl group was able to activate the dienophile's olefin bond in in the Diels-Alder reaction . After accomplishing its activation task , the acetyl group must be converted into the required isopropenyl substituent .

The Wittig reaction has been surveyed by Maercker and by House . The reader is referred to these reviews for useful information concerning experimental conditions and techniques , with many references provided to the original research literature .

Step 4 : Hydroboration of the two double bonds .

This is the second-most important step of the proposed route to l-(–)-menthol ; the Diels-Alder cyclization is undoubtedly the critical step , as most of the molecule’s carbon skeleton is assembled in it . Ordinary catalytic hydrogenation (by hydrogen) of the olefin bonds in intermediate 3 is unsatisfactory , as no stereochemical control would be possible . A more subtle , sophisticated hydrogenation of the two olefin bonds , one which permits a full control of the stereochemistry of the hydrogenated product , must be found . Fortunately , the technique of hydroboration seems custom-made for this application .

Hydroboration is a remarkably versatile , selective method for adding various substituents , including hydrogen , to the olefin bond . Several hydroboration reagents are available , including the simplest of them , diborane (B2H6) itself . The hydroboration agent recommended in this menthol scheme is thexylborane , whose bulky alkyl group will increase the selectivity of the addition reaction to intermediate 3 . Thexylborane is usually generated in situ by the addition of diborane to the commercially available alkene 2,3-dimethyl-2-butene (b.p. 73 C) :

(CH3)2C=C(CH3)2 + B2H6 ------------ (THF , 25 C) ---------> (CH3)2CH–CH(CH3)2–BH2 .

Diborane , and alkylborane derivatives like thexylborane , will add preferentially to less sterically hindered carbon atoms at double bonds :

CH2=CR1R2 >faster than> CHX=CR1R2 >faster than> CXY=CR1R2 ,

where X , Y , R1 , and R2 are various non-hydrogen substituents . The addition of B–H to the alkene double bond also occurs with a cis geometry , which will be of critical importance in establishing the correct stereochemistry in the cycloborane pre-menthol intermediate .

The hydrogenating behaviour of boranes is nicely illustrated in the following two examples of additions of thexylborane to limonene . The first one is provided by Brown and Pfaffenberger :

Note the transformation of (+)-limonene into ()-carvomenthol . The implication here is that l-(–)-5-acetoxy-limonene may be transformed into d-(+)-menthyl acetate in the hydroboration step . If so , then the Diels-Alder and subsequent steps would have to be repeated to obtain d-(+)-5-acetoxy-limonene for conversion into the desired l-(–)-menthyl acetate .

In the second example from Pelter and co-workers , the cycloborane intermediate was carbonylated to the corresponding bicyclic ketone by treatment with cyanide , trifluoroacetic anhydride , and an oxidizing agent :

These two examples illustrate the hydroboration technique suggested for the hydrogenation of 5-acetoxy-limonene . The beauty of the method is that the first step of the hydroboration , the addition of the thexylborane to the less-hindered isopropenyl function , will stereochemically assist the second step , the addition of the second B–H hydrogen to the ring olefin bond in its less-hindered position , and on the same face of the molecule , its “underneath” (as sketched) . And , since the B–H addition is cis , the limonene methyl group is pushed “upward” to the upper side of the molecule . It will thus have the correct stereochemistry relative to the “down” isopropyl group , as required for menthol .

Protonolysis of alkylboranes to the corresponding hydrocarbons – in effect , “hydrogenating” them – requires surprisingly vigorous conditions . The standard technique consists of refluxing the alkylborane in diglyme [diethylene glycol dimethyl ether , b.p. 162 C] , together with an excess of propionic acid (b.p. 141 C) at 160 C for 2–3 hours .

The final step of the proposed synthesis would be the alkaline saponification of the menthyl acetate to menthol . This might be accomplished with aqueous or methanolic NaOH . Saponification was included with the hydroboration reactions to make a more compact sketch ; however , it might be advisable in actual practice to extract , purify , and characterize the l-(–)-menthyl acetate . As the ester is well known the experimentation could end there , but it might still be fun to complete the synthesis at menthol , if for no other reason than to inhale the cooling smell of success ! I hasten to add that all the spectroscopic analyses , melting point , and polarimetry measurements should , of course , be carried out on the final product to ensure its correct identification as genuine l-(–)-menthol .

In conclusion , the proposed synthesis route to l-(–)-menthol , analogous to Vig’s earlier synthesis of dipentene , is fairly simple and straightforward , and has a good chance of success ; at least , I think it “looks good on paper”. The researcher can be , indeed often is , surprised and disappointed in actual laboratory practice , but that should be an incentive for the unleashing of creative energies to overcome experimental problems . The designing of this synthesis route to l-(–)-menthol was very educational and mentally stimulating for me , as I hope it has been for readers to study and think about .

 

References and Notes

 

Recommended textbooks : R.S. Ward , Selectivity in Organic Synthesis , John Wiley , Chichester (UK) , 1999 ; R.S. Atkinson , Stereoselective Synthesis , John Wiley , Chichester (UK) , 1995 .

classic organic reactions : Step 1 , the Darzens synthesis of unsaturated ketones (1910) : the French chemist Georges A. Darzens (1867-1954) (PDF , 504 KB ; Note : this file can be opened only with Adobe Acrobat Reader v. 6 or later . If desired , this application can be downloaded for free from Oldversion.com) is best known for his glycidic ester condensation . Step 2 , the Diels-Alder cyclization reaction (1928) : the German chemists Otto Diels (1876-1954) and Kurt Alder (1902-1958) won the 1950 Nobel Prize in Chemistry for their famous reaction . Step 3 , the phosphorus ylid olefination reaction (1954) : the German chemist Georg Wittig (1897-1987) shared the 1979 Nobel Prize in Chemistry (with H.C. Brown) for his discovery and development of this valuable synthetic reaction . Step 4 , the hydroboration reactions of olefins (1961) : the American chemist Hebert C. Brown (1912-2004) shared the 1979 Nobel Prize in Chemistry (with Georg Wittig) for his pioneering work in organoborane chemistry .

chemical specialties market : anon. , “For Cooling Menthol , It’s a Hot Marketing Battle”, Chemical Week , November 14th , 1979 ; p. 49 ; M.D. Rosenzweig , “Aroma Makers Scent a Business Upturn”, Chemical Engineering , March 15th , 1976 ; pp. 55-56 . The industrial (bulk) cost of “natural menthol”, i.e. l-(–)-menthol , was quoted at $19.00 U.S. per kilogram (Chemical Market Reporter , March 29th , 2004) . A more recent reference : “Menthol : A Breath of Fresh Air in a Dynamic Market” (web page) . See also : J.M. Derfer and M.M. Derfer , “Terpinoids”, pp. 709-762 in the Kirk-Othmer Encyclopedia of Chemical Technology , 3rd edition , vol. 22 , M. Grayson and D. Eckroth (eds.) , John Wiley , New York , 1983 ; menthol is reviewed on pp. 742-745 .

peppermint oils: D.L. Manuale et al. , “Synthesis of Liquid Menthol by Hydrogenation of Dementholized Peppermint Oil Over Ni Catalysts”, Quim. Nova 33 (6) , pp. 1231-1234 (2010) [PDF , 252 KB] .

levo-(–)-menthol : The absolute configuration of (1R,2S,5R)-(–)-menthol : W. Klyne and J. Buckingham , Atlas of Stereochemistry , Absolute Configurations of Organic Molecules , Chapman and Hall , London (UK) , 1974 ; A26 , p. 30 . Derfer and Derfer (above) provide the structural formula used in this text for l-(–)-menthol (their p. 743) .

hydrogenation of thymol : A.F. Thomas , “The Synthesis of Monoterpenes”, pp. 1-195 in The Total Synthesis of Natural Products , vol. 2 , J. ApSimon (ed.) , John Wiley , New York , 1973 ; p. 125 .

Chemical Engineering : J.C. Davis , “L-Menthol Synthesis Employs Cheap , Available Feedstocks”, Chemical Engineering , May 22nd , 1978 ; pp. 62-63 . This described the Haarman-Reimer [now Symrise] process for the industrial synthesis of racemic and levo-menthol . See also the web page , “(–)-Menthol Synthesis from m-Cresol / Thymol”, from the website , “Menthol – A Cool Place”, page 9 , Leffingwell & Associates , at http://www.leffingwell.com/menthol9/menthol9.htm . This excellent website has descriptions of almost a dozen other methods for synthesizing l-menthol from various starting materials , as well as web pages about fascinating organic compounds that , like menthol , produce a strong cooling sensation in the human nose when their odor is inhaled .

monoalkylated product : W.S. Calcott , J.M. Tinker , and V. Weinmayr , “Hydrofluoric Acid As a Condensing Agent . II . Nuclear Alkylations in the Presence of Hydrofluoric Acid”, J. Amer. Chem. Soc. 61 (5) , pp. 1010-1015 (1939) . The alkylation of m-cresol is described on p. 1013 .

selectively crystallize : The Haarmann-Reimer method of separating the l-()- and d-(+)-menthyl benzoate enantiomers is reminiscent of an organic experiment in which the enantiomers of 2-octanol are resolved by conversion into the “half-phthalate ester”, followed by salt formation with the optically active alkaloid brucine . The diastereomeric brucine salts can then be selectively precipitated and filtered from solution , followed by alkaline treatment to release the half-phthalate esters , then saponify them to produce the separate 2-octanol enantiomers : B.S. Furniss et al. , “Resolution of () Octan-2-ol”, Vogel’s Textbook of Practical Organic Chemistry , 4th edition , Longman , London (UK) , 1978 ; pp. 578-580 . Two other resolutions of racemic compounds in this volume : a-methylbenzylamine by L-(+)-tartaric acid , pp. 577-578 , and DL-alanine by selective enzymatic consumption of an enantiomer , pp. 580-581 . The technique of diastereomeric salt formation , such as with a carboxylic acid and amine , is usually referred to as the Pasteur method of resolution , named after the great French organic chemist Louis Pasteur (1822-1895) , who first developed it , and who was an early investigator of chirality in organic molecules (tartaric acid in 1848) .

Vig and coworkers : O.P. Vig , K.L. Matta , A. Lal , and I. Raj , “Synthesis of Dipentene and a-Terpinene”, Chem. Abs. 61 , 1895e (1964) . Original article , which I haven’t been able to access : J. Indian Chem. Soc. 41 (2) , pp. 142-144 (1964) .

synthesis of 1-chloro-3-pentanone : W. Schoeller and C. Zllner , “Ketone and Method of Making Same”, U.S. Patent 1737203 , November 26th , 1929 [PDF , 184 KB] .

acylation of olefins : E.E. Royals and C.M. Hendry , “The Acylation of Olefins . I . The Acetylation of Cyclohexene”, J.Org. Chem. 15 (6) , pp. 1147-1154 (1950) . See also : A.C. Byrns and T.F. Doumani , “Ketone Synthesis , The Condensation of Acid Anhydrides With Olefins” , Ind. Eng. Chem. 35 (3) , pp. 349-353 (1943) . The latter authors considered anhydrous zinc chloride to be the best catalyst of those they studied in the acylation reactions with acetic anhydride .

dehydrohalogenated by suitable basic reagents : For example , using 2,4,6-collidine to dehydrohalogenate 2-chloro-2-methylcyclohexanone : E.W. Warnhoff , D.G. Martin , and W.S. Johnson , 2-Chloro-2-methylcyclohexanone and 2-Methyl-2-cyclohexenone”, Org. Synth. Coll. Vol. 4 , pp. 162-166 (1963) [PDF , 155 KB] .

acetylene gas : The Darzens acylation of acetylene by acetyl chloride (using AlCl3 as the Lewis acid catalyst) to produce b-chlorovinyl methyl ketone was described by : J.R. Catch , D.F. Elliott , D.H. Hay , and E.R.H. Jones , “Halogenated Ketones . Part IV . The Application of the Friedel-Crafts Reaction to the Preparation of Halogenated Aliphatic Ketones”, J. Chem. Soc. 1948 , pp. 278-281 ; C.C. Price and J.A. Pappalardo , “The Synthesis of Some a,b-Unsaturated Aldehydes”, J. Amer. Chem. Soc. 72 (6) , pp. 2613-2615 (1950) ; W.R. Benson and A.E. Pohland , “Trans-b-Chlorovinyl Ketones and Trans-b-(Acylvinyl)trimethylammonium Chlorides”, J. Org. Chem. 29 (2) , pp. 385-391 (1964) .

Stereochemical retention : W.E. Bachmann and L.B. Scott , “The Reaction of Anthracene with Maleic and Fumaric Acid and Their Derivatives and with Citraconic Anhydride and Mesaconic Acid”, J. Amer. Chem. Soc. 70 (4) , pp. 1458-1461 (1948) .

para-to-ortho ratio : E.F. Lutz and G.M. Bailey , “Regulation of Structural Isomerism in Simple Diels-Alder Adducts”, J. Amer. Chem. Soc. 86 (18) , pp. 3899-3901 (1964) .

Friedel-Crafts catalysts : P. Yates and P. Eaton , “Acceleration of the Diels-Alder Reaction by Aluminum Chloride”, J. Amer. Chem. Soc. 82 (16) , pp. 4436-4437 (1960) ; G.I. Fray and R. Robinson , “Catalysis of the Diels-Alder Reaction”, J. Amer. Chem. Soc. 83 (1) , p. 249 (1961) ; T. Inukai and M. Kasai , “Diels-Alder Reactions of Acrylic Acid Derivatives Catalyzed by Aluminum Chloride”, J. Org. Chem. 30 (10) , pp. 3567-3569 (1965) . See also : J.B. Hall and J.M. Sanders , “Perfume Compositions and Perfume Articles Containing One Isomer of an Octahydrotetramethyl Acetonapthone”, U.S. Patent 3,929,677 to International Flavors & Fragrances Inc. (December 30 , 1975) , in which catalysed Diels-Alder reactions are described . [PDF , 640 KB . Note : this file can be opened only with Adobe Acrobat Reader v. 6 or later] .

Nafion H : G.A. Olah , D. Meidar , and A.P. Fung , “Synthetic Methods and Reactions ; 59 . Catalysis of Diels-Alder Reactions by Nafion-H Perfluorinated Resinsulfonic Acid”, Synthesis , April 1979 , pp. 270-271 .

Wurster Blue salt : D.J. Bellville , D.D. Wirth , and N.L. Bauld , “The Cation-Radical Catalyzed Diels-Alder Reaction”, J. Amer. Chem. Soc. 103 (3) , pp. 718-720 (1981) ; D.J. Bellville and N.L. Bauld , “Selectivity Profile of the Cation Radical Diels-Alder Reaction”, J. Amer. Chem. Soc. 104 (9) , pp. 2665-2667 (1982) ; N. L. Bauld , J. T. Aplin , W. Yueh , and A. Loinaz , “A Non-Outer Sphere Mechanism for the Ionization of Aryl Vinyl Sulfides by Triarylaminium Salts”, J. Amer. Chem. Soc. 119 (47) , pp. 11381-11389 (1997) .

diazaaluminolidine : E.J. Corey , R. Imwinkelried , S. Pikul , and Y. B. Xiang ,“Practical Enantioselective Diels-Alder and Aldol Reactions Using a New Chiral Controller System”, J. Amer. Chem. Soc. 111 (14) , pp. 5493-5495 (1989) ; E.J. Corey , N. Imai , and S. Pikul , “Catalytic Enantioselective Synthesis of a Key Intermediate for the Synthesis of Prostanoids”, Tet. Lett. 32 (51) , pp. 7517-7520 (1991) ; E.J. Corey , S. Sarshar , and J. Bordner , “X-ray Crystallographic and NMR Studies on the Origins of High Enantioselectivity in Diels-Alder Reactions Catalyzed by a Chiral Diazaaluminolidine”, J. Amer. Chem. Soc. 114 (20) , pp. 7938-7939 (1992) ; E.J. Corey , S. Sarshar , and D-H. Lee , “First Example of a Highly Enantioselective Catalytic Diels-Alder Reaction of an Achiral C2v-Symmetric Dienophile and an Achiral Diene”, J. Amer. Chem. Soc. 116 (26) , pp. 12089-12090 (1994) ; E.J. Corey , “New Enantioselective Routes to Biologically Interesting Compounds”, Pure & Appl. Chem. 62 (7) , pp. 1209-1216 (1990) [PDF , 550 KB ; enantioselective Diels-Alder reactions are discussed on p. 1211] ; anon. , “Asymmetric Diels-Alder Reactions” [PDF , 1096 KB] .

Chiral asymmetry-inducing catalysts with boron as the electrophilic center have also been successfully used (96% product yield with a 99% enantiomeric excess) in asymmetric Diels-Alder cyclizations ; for example : S. Mukherjee and E.J. Corey , “ Highly Enantioselective Diels-Alder Reactions of Maleimides Catalyzed by Activated Chiral Oxazaborolidines”, Org. Lett. 12 (3) , pp. 632-635 (2010) .

Surveys of catalysed Diels-Alder reactions : R.S. Ward , Selectivity in Organic Synthesis , op. cit. : Lewis acid catalysed Diels-Alder reactions ; pp. 30-38 , chiral catalysts pp. 35-36 ; R.S. Atkinson , Stereoselective Synthesis , op. cit. : Lewis acid catalysed Diels-Alder reactions , pp. 156-172 ; chiral catalysts , pp. 443-448 ; F. Fringuelli and A. Taticchi , The Diels-Alder Reaction , Selected Practical Methods , John Wiley , Chichester (UK) , 2002 : Lewis acid catalysed Diels-Alder reactions , pp. 99-142 ; chiral catalysts , pp. 116-122 ; L.A. Paquette , “Asymmetric Cycloaddition Reactions”, Ch. 7 , pp. 455-501 in Asymmetric Synthesis , vol. 3 , Stereodifferentiating Addition Reactions , Part B , J.D. Morrison (ed.) , Academic Press , Orlando (FL) , 1984 ; asymmetric Diels-Alder reactions , pp. 456-482 ; chiral catalysts , pp. 477-478 .

optically active polybenzofuran : G. Natta , M. Farina , M. Peraldo , and G. Bressan , “Asymmetric Synthesis of Optically Active Di-isotactic Polymers from Cyclic Monomers”, Makromol. Chem. 43 (1) , pp. 68-75 (1961) ; M. Farina and G. Bressan , “Optically Active Polymers : Some New Results and Remarks on the Asymmetric Polymerization of Benzofuran”, Makromol. Chem. 61 (1) , pp. 79-89 (1963) ; G. Bressan and M. Farina , “Optically Active Polybenzofuran”, pp. 635-638 in Macromolecular Syntheses , Coll. Vol. 1 , J.A. Moore (ed.) , John Wiley , New York , 1977 .

Maercker : A. Maercker , “The Wittig Reaction”, Ch. 3 , pp. 270-490 in Org. React. 14 , A.C. Cope et al. (eds.) , John Wiley , New York , 1965 .

House : H.O. House , Modern Synthetic Reactions , 2nd edition , W.A. Benjamin , Menlo Park (CA) , 1972 . The Wittig reaction is reviewed on pp. 628-709 . See also : H.B. Hopps and J.H. Biel , “The Wittig Reaction”, Aldrichchimica Acta 2 (2) , pp. 3-6 (1969) [PDF , 2760 KB ; the entire Issue 2 must be downloaded to obtain the article] .

occurs with a cis geometry : House (preceding ref.) , p. 109 :

“The addition of borane to a double bond has been found to occur in a cis manner from the less hindered side of the double bond ……”.

Hydroboration chemistry is reviewed on pp. 106-130 .

Brown and Pfaffenberger : H.C. Brown and C.D. Pfaffenberger , “Thexylborane as a Convenient Reagent for the Cyclic Hydroboration of Dienes . Stereospecific Syntheses via Cyclic Hydroboration”, J. Amer. Chem. Soc. 89 (21) , pp. 5475-5477 (1967) .

transformation of (+)-limonene : E.E. Royals and S.E. Horne Jr. , “Conversion of d-Limonene to l-Carvone”, J. Amer. Chem. Soc. 73 (12) , pp. 5856-5857 (1951) . Their process is sketched as follows :

In this reaction scheme we see that while the R configuration of the asymmetric carbon remains unchanged throughout all of the chemical transformations , the optical rotation of the l-(–)-carvone product as measured in a polarimetry tube has been reversed from that of the d-(+)-limonene starting material . A similar situation may occur in the hydroboration step discussed above . That is , l-(–)-5-acetoxy-limonene (3) might provide d-(+)-menthyl acetate rather than the desired l-(–)- enantiomer .

Four other syntheses of l-(–)-carvone from d-(+)-limonene : S.M. Linder and F.P. Greenspan , “Reactions of Limonene Monoxide . The Synthesis of Carvone”, J. Org. Chem. 22 (8) , pp. 949-951 (1957) ; C. Bordenca , R.K. Allison , and P.H. Dirstine , “l-Carvone from d-Limonene”, Ind. Eng. Chem. 43 (5) , pp. 1196-1198 (1951) ; their procedure , which was published earlier in 1951 than that of Royals and Horne , was quite similar to it , but had an overall yield of l-(–)-carvone of 35% , roughly half of the latter synthesis . Bordenca and coworkers used the very cheap urea to convert their limonene nitrosochloride into carvoxime in 99% yield , and they also successfully hydrolysed the carvoxime to carvone using 6N sulfuric acid (pH ~ 0.9) , but steam-distilling the carvone as it was formed (in 54% yield) , to prevent its tautomerization to carvacrol ; R. Reitsema , “Nitrosochloride Syntheses and Preparation of Carvone”, J. Org. Chem. 23 (12) , pp. 2038-2039 (1958) (a simplified preparation of the nitrosochloride intermediate from limonene , aqueous sodium nitrite , and hydrochloric acid) ; O.S. Rothenberger , S.B. Krasnoff , and R.B. Rollins , “Conversion of (+)-Limonene to ()-Carvone : An Organic Laboratory Sequence of Local Interest”, J. Chem. Educ. 57 (10) , p. 741 (1980) .

Pelter and co-workers : A. Pelter , M.G. Hutchings , and K. Smith , “1,1,2-Trimethylpropyl-dialkylcyanoborates as Intermediates for the Synthesis of Symmetrical , Unsymmetrical , Functionalized , and Cyclic Ketones”, J.C.S. Chem. Commun. 1971 , pp. 1048-1050 .

Protonolysis of alkylboranes : H.C. Brown , Organic Syntheses via Boranes , John Wiley , New York , 1975 ; protonolysis is discussed on pp. 81-82 , with an experimental description for the hydroboration reduction of (–)-b-pinene to (–)-pinane . See also : G. Zweifel and H.C. Brown , “Hydroboration of Terpenes . II . The Hydroboration of a- and b-Pinene – The Absolute Configuration of the Dialkylborane from the Hydroboration of a-Pinene” , J. Amer. Chem. Soc. 86 (3) , pp. 393-397 (1964) . Protonolysis of the intermediate cyclic borane with propionic acid in refluxing diglyme is described on pp. 396-397 .

 

 

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