Organic Chemistry Laboratory I
Acid Catalyzed Isomerization of Carvone to Carvacrol
Experiment Description and Background

Introduction
Students will work in pairs to prepare carvacrol from carvone through a multi-step process that is catalyzed by acid.   Carvacrol is generated from carvone through a series of four distinct reaction steps:
1) protonation of an alkene to generate  a carbocation, 2) rearrangement of the carbocation, 3) generation of an alkene from the rearranged carbocation, and 4) enolization to the phenol .  Each step of the transformation is outlined in the reaction mechanism below.  The reaction will be monitored by TLC and a percent yield of the product will be determined.  Spectra of the carvacrol product will be generated (IR) or provided (1H NMR), analyzed for consistency with the structure of carvacrol and compared with spectra data of the starting carvone. 



Figure 1:  Mechanism of the Acid-Catalyzed Isomerization of Carvone to Carvacrol
Carvone and Carvacrol :  Natural Products and Physical Properties
Carvone is a terpene natural product found in spearmint, caraway and dill.  This terpene has also been isolated from the peel of mandarian oranges.  Carvone contains a chiral center and occurs as both its R and S enantiomers in natural products. The dominant enantiomer in spearmint is the R-isomer, while the S-isomer is found in caraway.  Carvone is used extensively in the food industry as a flavoring and has also been marketed for use in aromatherapy and other alternative medicinal products.  In the pharmaceutical industry, carvone serves as a precursor in numerous synthesis of  complex, chiral drugs.  Carvone is a liquid at room temperature with a boiling point of 2790C.   It is non-polar and contains a conjugated ketone and an unconjugated alkene. 
 

Carvacrol is the major component of a number of natural products including thyme, oregano and oil of origanum.  (An isomer of carvacrol is a major component in the mouthwash, Listerine).  Some unsubstantiated reports claim that carvacrol is an effective antibiotic.  Carvacrol is a semi-solid at room temperature (~200C) and has a boiling point of 236-2370C.  Carvacrol is also relatively non-polar but has an acidic phenol functional group. 
The Mechanism of the Acid-Catalyzed Conversion of Carvone to Carvacrol
Carvone contains a ketone and two alkene functional groups.  One of the alkenes is conjugated with the ketone (called a conjugated enone); the other alkene is not conjugated. Treatment of carvone with strong acid promotes reaction of the non-conjugated alkene to react with the acid to generate a carbocation, the first step of the reaction illustrated in Figures 1 and 2.  In this step, the pi electrons of the alkene react with a proton.  A new C-H bond is generated between one of the carbons of the alkene (C2 in the Figure 2 below) and the proton, leaving behind a carbocation on the other carbon atom of the alkene (C1 in Figure 2). The reaction occurs with the regiochemistry shown to give the more stable tertiary carbocation (rather than the less stable primary carbocation), consistent with Markovnikov additon observed in electrophilic addition reactions.  


Figure 2:  Step One of the Reaction:  Protonation of the Non-Conjugated Alkene of Carvone

Step 2 of the Reaction:  Carbocation Rearrangement
The tertiary carbocation that is generated in step one continues to react by undergoing a rearrangement.  This rearrangement involves migration of a hydrogen atom from the C1 carbon (depicted in Figure 3 below) to the C2 carbon.  This migration of a hydrogen atom is called a 1,2 -hydride shift, referring to the shift in bonding of a H from one carbon (C1) to an adjacent carbon (C2).  The hydrogen atom takes electrons from the C1-H bond and uses those electrons to form a new bond with the C2 carbon.  The net result is that a new carbocation is generated on C1.  Carbocation rearrangements generally occur only if the resulting carbocation is equally stable or more stable that the original carbocation.  The new carbocation generated in this step of the reaction is a tertiary carbocation, equivalent in stability to the original carbocation. 



Figure 3:  Step 2 of the Reaction:  Carbocation Rearrangement (1,2-hydride shift)

Step 3 of the Reaction:  Formation of a Conjugated Diene
The rearranged carbocation generated in step 3 continues to react to generate a conjugated diene.  In this step of the reaction, electrons from a C-H bond (C1 in Figure 4), adjacent to the carbocation (C2) are used to form a new pi bond.   The H atom of this bond loses its electrons and becomes a proton (H+), thus regenerating the acid used in step one and making the overall reaction catalytic (See section below on catalyzed reactions).  A new alkene is generated in this step of the reaction that is conjugated with the aleken of the enone functional group.  The conigated diene is significantly more stable that the tertiary carbocation.


Figure 4:  Step 3 of the Reaction:  Formation of the Conjugated Diene

Step 4 of the Reaction:  Generation of Carvacrol by Enolization
The conjugated diene undergoes one final step in the reaction to generate carvacrol.  In this last step, the ketone is converted to a phenol in a process referred to as enolization.  Enolization is initiated when one of the lone pairs on the oxygen of the carbonyl group accepts a proton to generate an oxonium ion (a positively charged oxygen atom).  The electrons of the alpha C-H bond shift over to become a new pi bond between the alpha carbon (C1 in Figure 5 below) and the carbonyl carbon (C2), and the pi electrons of the carbonyl group become a lone pair on the oxygen, removing the formal charge on oxygen and generating the phenol. 

Figure 5:  Step 4 of the Reaction:  Enolization to Form Carvacrol
Thermodynamics and Kinetics of the Reaction
Generation of carvacrol from carvone under acid-catalysis is a thermodynamically-favorable reaction.  The product (carvacrol) is more stable than the starting material (carvone).   Carvone has a conjugated pi system  and its stability is enhanced through resonance, however the aromatic ring of carvacrol imparts even more stablization to the product.  The rate-determining step of the reaction (slow step) is the first step that involves formation of the carbocation from the unconjugated alkene of carvone.  Rearrangement of this carbocation to a second, tertiary carbocation occurs in the next, fast step, followed by loss of a hydrogen to form a stable, conjugated dienone.  The dienone then enolizes in the forth step to give the aromatic product, carvacrol.  The thermodynamics and kinetics of the reaction are illustrated in the reaction energy diagram for this process, shown in Figure 6.


Figure 6:  Reaction Energy Diagran for the Acid-Catalyzed Conversion of Carvione to Carvacrol

The isomerization of carvone to carvacrol is an acid catalyzed reaction.  A catalyst is a special kind of reagent that is used to initiate a reaction by lowering the activation energy of the rate determining step of the reaction.  The catalyst is not a permanent reagent in the reaction , but rather is used temporarily and is eventually regenerated in the reaction.  The acid catalyst in this react is used in step 1 of the reaction, the rate-determining step. The acid is then regenerated in step 3 of the reaction when the conjugated diene is formed. 
Characterization of the Reaction Product by Spectroscopic Analysis
The reaction of carvone with sulfuric acid to form carvacrol may be monitored by TLC.  The phenol functional group of the carvacrol impacts H-bonding characteristics in the product that are not present in the starting material  and thus the product would be expected to have a lower Rf value when analyzed by TLC on silica gel.  Comparison of carvone with the reaction mixture allows for qualitative determination of the reaction progress.  Both the starting carvone and the carvacrol product can be detected easily on a TLC plate by both iodine and UV light, since both contain conjugated systems.

IR spectroscopic analysis of the reaction mixture and the starting carvone allows for assessment of the reaction .  The reactant carvone contains a conjugated ketone which will have a characteristic peak in its IR spectrum in the range of 1650-1720cm-1.  Conversely, the IR spectrum of the carvacrol will lack the carbonyl peak but will contain peaks consistent with the phenolic OH and the aromatic ring. 

The proton NMR spectra of carvone and carvacrol will also allow the product of this reaction to be distinghuished from the starting material.  The proton NMR spectrum of carvacrol should contain characteristic peaks in the aromatic region of the spectrum that correspond to the three aromatic protons.  Two of the aromatic protons should appear as doublets and the third proton should appear in this region of the spectrum as a singlet.  The benzylic methyl will appear as a singlet in the region between  1.5-2.5 ppm in the spectrum, and the isporopyl group should give rise to a doublet (0-1.5ppm) and a multiplet ( 1.5-2.5ppm).   The spectrum of carvone will contain vinylic protons but no aromatic resonances.