Question

Outline all steps in a possible laboratory synthesis of each of the following compounds from cyclohexanol and any necessary aliphatic, aromatic, or inorganic reagents. (a) cyclohexanone \(\left(\mathrm{C}_{6} \mathrm{H}_{10} \mathrm{O}\right)\) (b) bromocyclohexane (c) 1 -methylcyclohexanol (d) 1 -methylcyclohexene (e) trans-2-methylcyclohexanol (f) cyclohexylmethylcarbinol (g) trans \(-1,2\) -dibromocyclohexane (h) cyclohexanecarboxylic acid (i) adipic acid \(\mathrm{HOOC}\left(\mathrm{CH}_{2}\right)_{4} \mathrm{COOH}\)

Short answer

To summarize, the steps for synthesizing the given compounds are: (a) Cyclohexanone: Oxidation of cyclohexanol using potassium dichromate and sulfuric acid. \[ \mathrm{C}_{6} \mathrm{H}_{11} \mathrm{OH} + \mathrm{K}_{2} \mathrm{Cr}_{2} \mathrm{O}_{7} + \mathrm{4H}^{+} \rightarrow \mathrm{C}_{6} \mathrm{H}_{10} \mathrm{O} + \mathrm{Cr}_{2}\left(\mathrm{SO}_{4}\right)_{3} + \mathrm{7H}_{2} \mathrm{O} + \mathrm{2K}^{+} \] (b) Bromocyclohexane: Conversion of cyclohexanol to cyclohexyl bromide using phosphorus tribromide. \[ \mathrm{C}_{6} \mathrm{H}_{11} \mathrm{OH} + \mathrm{PBr}_{3} \rightarrow \mathrm{C}_{6} \mathrm{H}_{11} \mathrm{Br} + \mathrm{H}_{2} \mathrm{O} + \mathrm{H}_{2} \mathrm{PO}_{3} \] (c) 1-methylcyclohexanol: Conversion of cyclohexanol to cyclohexene, followed by hydroboration-oxidation using diborane, alkylboranes, hydrogen peroxide, and sodium hydroxide. \[ \mathrm{C}_{6} \mathrm{H}_{10} \mathrm{=} \mathrm{CH}_{2} + \ce{BH3-THF} \xrightarrow{\mathrm{H2O2, NaOH}} \mathrm{C}_{6} \mathrm{H}_{11} \mathrm{OCH}_{3} \] (d) 1-methylcyclohexene: Conversion to 1-methylcyclohexanol, then dehydration using concentrated sulfuric acid or phosphoric acid. \[ \mathrm{C}_{6} \mathrm{H}_{11} \mathrm{OCH}_{3} \xrightarrow{\mathrm{H2SO4, \Delta}} \mathrm{C}_{6} \mathrm{H}_{10} \mathrm{CHCH}_{2} + \mathrm{H}_{2} \mathrm{O} \] (e) trans-2-methylcyclohexanol: Conversion to 1-methylcyclohexanol, followed by epoxidation using m-chloroperbenzoic acid and acid-catalyzed ring opening with water. (f) Cyclohexylmethylcarbinol: Preparation of Grignard reagent from cyclohexanol, reaction with formaldehyde and acidic workup. \[ \mathrm{C}_{6} \mathrm{H}_{11} \mathrm{MgBr} + \mathrm{HCHO} \xrightarrow{\mathrm{H2O}} \mathrm{C}_{6} \mathrm{H}_{11} \mathrm{CHOHCH}_{3} \] (g) trans-1,2-dibromocyclohexane: Bromination of carbon-carbon double bond using bromine and carbon tetrachloride. \[ \mathrm{C}_{6} \mathrm{H}_{10} \mathrm{=} \mathrm{CH}_{2} + \mathrm{Br}_{2} \rightarrow \text{trans-1,2-dibromocyclohexane} \] (h) Cyclohexanecarboxylic acid: Oxidation to cyclohexanone, then Baeyer-Villiger oxidation with peroxy acid. \[ \mathrm{C6H10O} + \text{mCPBA} \rightarrow \mathrm{C6H11O2} + \text{mCPB} \] (i) Adipic acid: Oxidation with potassium permanganate and dilute sodium hydroxide. \[ \mathrm{C}_{6} \mathrm{H}_{10} \mathrm{=} \mathrm{CH}_{2} + \mathrm{4KMnO}_{4} + \mathrm{6NaOH} \rightarrow \mathrm{HOOC}\left(\mathrm{CH}_{2}\right)_{4} \mathrm{COOH} + \mathrm{4MnO}_{2} + \mathrm{4KOH} + \mathrm{5H}_{2} \mathrm{O} \]

Step-by-step solution

Oxidation of cyclohexanol to cyclohexanone

To synthesize cyclohexanone from cyclohexanol, we need to oxidize the alcohol group to a ketone group. This can be done by using an oxidizing agent like potassium dichromate (K2Cr2O7) in the presence of a diluted acid like sulfuric acid (H2SO4). The balanced equation for this reaction is as follows: \[ \mathrm{C}_{6} \mathrm{H}_{11} \mathrm{OH} + \mathrm{K}_{2} \mathrm{Cr}_{2} \mathrm{O}_{7} + \mathrm{4H}^{+} \rightarrow \mathrm{C}_{6} \mathrm{H}_{10} \mathrm{O} + \mathrm{Cr}_{2}\left(\mathrm{SO}_{4}\right)_{3} + \mathrm{7H}_{2} \mathrm{O} + \mathrm{2K}^{+} \] (b) bromocyclohexane

Conversion of cyclohexanol to cyclohexyl bromide

To synthesize bromocyclohexane from cyclohexanol, we use a hydrohalogenation reaction involving phosphorus tribromide (PBr3) as a reagent. This will convert the alcohol group of cyclohexanol to a bromide group. The reaction is as follows: \[ \mathrm{C}_{6} \mathrm{H}_{11} \mathrm{OH} + \mathrm{PBr}_{3} \rightarrow \mathrm{C}_{6} \mathrm{H}_{11} \mathrm{Br} + \mathrm{H}_{2} \mathrm{O} + \mathrm{H}_{2} \mathrm{PO}_{3} \] (c) 1 -methylcyclohexanol

Conversion of cyclohexanol to cyclohexene

To synthesize 1-methylcyclohexanol, we first need to convert cyclohexanol to cyclohexene, which requires the dehydration of cyclohexanol by eliminating the \(\ce{-OH}\) group using a strong acid like concentrated sulfuric acid or phosphoric acid (H3PO4). The reaction is as follows: \[ \mathrm{C}_{6} \mathrm{H}_{11} \mathrm{OH} \xrightarrow{\mathrm{H2SO4, \Delta}} \mathrm{C}_{6} \mathrm{H}_{10} \mathrm{=} \mathrm{CH}_{2} + \mathrm{H}_{2} \mathrm{O} \]

Hydroboration-oxidation to form 1-methylcyclohexanol

Next, we perform a hydroboration-oxidation reaction with a mixture of diborane (\(\ce{B2H6}\)) and alkylboranes (\(\ce{BH3-THF}\)) with hydrogen peroxide (\(\ce{H2O2}\)) and sodium hydroxide (\(\ce{NaOH}\)). The reaction is as follows: \[ \mathrm{C}_{6} \mathrm{H}_{10} \mathrm{=} \mathrm{CH}_{2} + \ce{BH3-THF} \xrightarrow{\mathrm{H2O2, NaOH}} \mathrm{C}_{6} \mathrm{H}_{11} \mathrm{OCH}_{3} \] (d) 1 -methylcyclohexene

Conversion to 1-methylcyclohexanol (Refer to steps in part c)

First, convert cyclohexanol to 1-methylcyclohexanol by following the steps outlined in part (c) above.

Dehydration to form 1-methylcyclohexene

Next, we dehydrate 1-methylcyclohexanol using a strong acid like concentrated sulfuric acid or phosphoric acid (H3PO4), which will eliminate the \(\ce{-OH}\) group and form a double bond. The reaction is as follows: \[ \mathrm{C}_{6} \mathrm{H}_{11} \mathrm{OCH}_{3} \xrightarrow{\mathrm{H2SO4, \Delta}} \mathrm{C}_{6} \mathrm{H}_{10} \mathrm{CHCH}_{2} + \mathrm{H}_{2} \mathrm{O} \] (e) trans-2-methylcyclohexanol

Conversion to 1-methylcyclohexanol (Refer to steps in part c)

First, convert cyclohexanol to 1-methylcyclohexanol by following the steps outlined in part (c) above.

Stereospecific reaction to form trans-2-methylcyclohexanol

Perform an epoxidation reaction using m-chloroperbenzoic acid (mCPBA) and then acid-catalyzed ring opening with water to selectively produce the trans isomer. The reactions are as follows: \[ \mathrm{C}_{6} \mathrm{H}_{11} \mathrm{OCH}_{3} + \text{mCPBA} \rightarrow \text{Epoxide} \] \[ \text{Epoxide} + \mathrm{H}_{3} \mathrm{O}^{+} \rightarrow \text{trans-2-methylcyclohexanol} \] (f) cyclohexylmethylcarbinol

Grignard reagent preparation

To synthesize cyclohexylmethylcarbinol, we first need to prepare a Grignard reagent from cyclohexanol. Convert cyclohexanol to cyclohexyl bromide (refer to steps in part b) and then treat cyclohexyl bromide with magnesium (Mg) in ether to form a Grignard reagent: \[ \mathrm{C}_{6} \mathrm{H}_{11} \mathrm{Br} + \mathrm{Mg} \rightarrow \mathrm{C}_{6} \mathrm{H}_{11} \mathrm{MgBr} \]

Reaction with formaldehyde and acidic workup

Next, react the Grignard reagent with formaldehyde (HCHO) and subsequently perform an acidic workup with water to yield cyclohexylmethylcarbinol: \[ \mathrm{C}_{6} \mathrm{H}_{11} \mathrm{MgBr} + \mathrm{HCHO} \xrightarrow{\mathrm{H2O}} \mathrm{C}_{6} \mathrm{H}_{11} \mathrm{CHOHCH}_{3} \] (g) trans \(-1,2\) -dibromocyclohexane

Bromination of carbon-carbon double bond

First, convert cyclohexanol to cyclohexene (refer to steps in part c), and then carry out a bromination reaction using bromine (Br2) in the presence of carbon tetrachloride (CCl4) as solvent. This reaction will selectively produce the trans isomer of 1,2-dibromocyclohexane: \[ \mathrm{C}_{6} \mathrm{H}_{10} \mathrm{=} \mathrm{CH}_{2} + \mathrm{Br}_{2} \rightarrow \text{trans-1,2-dibromocyclohexane} \] (h) cyclohexanecarboxylic acid

Oxidation to cyclohexanone (Refer to steps in part a)

First, convert cyclohexanol to cyclohexanone by following the steps outlined in part (a) above.

Baeyer-Villiger oxidation with peroxy acid

Next, perform a Baeyer-Villiger oxidation using a peroxy acid like m-chloroperbenzoic acid (mCPBA) to yield cyclohexanecarboxylic acid, as shown in the following reaction: \[ \mathrm{C6H10O} + \text{mCPBA} \rightarrow \mathrm{C6H11O2} + \text{mCPB} \] (i) adipic acid \(\mathrm{HOOC}\left(\mathrm{CH}_{2}\right)_{4} \mathrm{COOH}\)

Oxidation with potassium permanganate

In order to synthesize adipic acid, first convert cyclohexanol to cyclohexene (refer to steps in part c), then treat cyclohexene with potassium permanganate (KMnO4) in dilute sodium hydroxide (NaOH). This results in oxidation of the double bond to form two carboxylic acid groups, yielding adipic acid: \[ \mathrm{C}_{6} \mathrm{H}_{10} \mathrm{=} \mathrm{CH}_{2} + \mathrm{4KMnO}_{4} + \mathrm{6NaOH} \rightarrow \mathrm{HOOC}\left(\mathrm{CH}_{2}\right)_{4} \mathrm{COOH} + \mathrm{4MnO}_{2} + \mathrm{4KOH} + \mathrm{5H}_{2} \mathrm{O} \]

Key concepts

Oxidation Reactions

Oxidation reactions are fundamental transformations in organic chemistry that involve the increase in the oxidation state of an atom or the loss of electrons. In the laboratory synthesis from the exercise, cyclohexanol is oxidized to cyclohexanone using potassium dichromate (K2Cr2O7) as an oxidizing agent. This reaction specifically converts an alcohol to a ketone, a common type of oxidation in organic synthesis.

Oxidizing reagents, like potassium dichromate, are often used under acidic conditions. It's vital to note that proper handling and disposal of these materials are essential, as they can be both toxic and environmentally harmful.

• Identify the type of functional group transformation.
• Use an appropriate oxidizing agent.
• Control reaction conditions to avoid over-oxidation.

Hydrohalogenation Reactions

Hydrohalogenation reactions involve the addition of hydrogen halides (HX) to alkenes or alkynes, resulting in halogenated hydrocarbons. In the synthesis of bromocyclohexane, cyclohexanol undergoes conversion to a halide using phosphorus tribromide (PBr3). This is a typical example of converting an alcohol to an alkyl halide.

The specific choice of reagent and conditions ensures that the alcohol is effectively swapped for a halogen, often resulting in a good yield.

• Select a suitable halogenating reagent for the alcohol group.
• Monitor the reaction to avoid polyhalogenation.

Hydroboration-Oxidation Reactions

The hydroboration-oxidation reaction is a two-step pathway to convert alkenes to alcohols. It proceeds via the anti-Markovnikov addition of boron and subsequently boron is replaced by a hydroxyl group. This reaction is showcased by the conversion of cyclohexene to 1-methylcyclohexanol. Diborane (B2H6) or borane-THF complex (BH3-THF) is used for hydroboration, followed by oxidation with hydrogen peroxide (H2O2) in the presence of sodium hydroxide (NaOH).

The regiochemistry and stereoselectivity of this reaction are crucial. For students, it's important to recognize that hydroboration-oxidation enables the formation of alcohols without rearrangements that typify other addition reactions.

• Understand anti-Markovnikov addition.
• Achieve selective hydroboration with borane complexes.
• Follow with oxidative workup to obtain the alcohol.

Dehydration Reactions

Dehydration reactions entail the loss of a water molecule from a reactant. In organic synthesis, such reactions are often employed to convert alcohols to alkenes. The example given for synthesis of 1-methylcyclohexene from 1-methylcyclohexanol showcases classic acid-catalyzed dehydration.

Strong acids like sulfuric or phosphoric acids act as catalysts, promoting the removal of water and formation of a double bond. This process is guided by the Zaitsev's rule where the more substituted alkene is often the major product.

• Use a strong acid catalyst for dehydration.
• Control temperature to direct the reaction course.
• Consider Zaitsev's rule in predicting major products.

Grignard Reactions

The Grignard reaction is a versatile method for forming carbon-carbon bonds. It involves the use of Grignard reagents, which are alkyl or aryl magnesium halides. The example of cyclohexylmethylcarbinol synthesis starts with the preparation of a Grignard reagent from bromocyclohexane. The reaction with formaldehyde then introduces a new carbon atom from the carbonyl group, eventually resulting in an alcohol after acidic workup.

Key to the process is ensuring the reactants and conditions are free of moisture, as Grignard reagents are highly reactive toward water.

• Prepare the Grignard reagent in an anhydrous environment.
• Carefully choose the carbonyl compound for the desired substitution pattern.
• Perform an acidic workup to obtain the alcohol.

Baeyer-Villiger Oxidation

The Baeyer-Villiger oxidation is a special type of organic reaction that transforms ketones into esters (or cyclic ketones into lactones). This conversion is achieved by using peroxy acids like m-chloroperbenzoic acid (mCPBA). In the exercise, cyclohexanone is converted into cyclohexanecarboxylic acid through a Baeyer-Villiger oxidation.

The process selects for the migration of the substituent that can best stabilize a positive charge. Understanding the migratory aptitude of different groups is crucial to predicting the outcome of the reaction.

• Choose an appropriate peroxy acid as the oxidant.
• Recognize the migration of the alkyl group based on stability.
• Realize that the oxygen atom is inserted next to the more substituted carbon.

Bromination Reactions

Bromination reactions involve the addition of bromine to unsaturated compounds like alkenes and alkynes. For the production of trans-1,2-dibromocyclohexane, an alkene undergoes bromination in a non-polar solvent like carbon tetrachloride (CCl4). This halogen addition reaction typically results in trans products due to the anti-addition mechanism.

Factors influencing bromination include the type of solvent used and the nature of the alkene. Students should appreciate the stereospecificity of this reaction and the role of bromine as an electrophile.

• Ensure the use of elemental bromine in a suitable solvent.
• Understand the anti-addition mechanism for trans product formation.

Epoxidation Reactions

Epoxidation reactions introduce an oxygen atom in the form of an epoxide to an alkene, thus creating a three-membered cyclic ether. In the text exercise, an epoxidation reaction using m-chloroperbenzoic acid (mCPBA) is followed by acid-catalyzed ring opening to selectively produce trans-2-methylcyclohexanol.

Epoxidation reactions are stereospecific and maintain the geometry of the starting alkene. They are often followed by nucleophilic ring-opening under acidic or basic conditions to give vicinal diols or halohydrins.

• Utilize a peracid such as mCPBA for epoxidation.
• Control reaction conditions for stereoselective outcomes.
• Consider subsequent ring-opening for further transformations.