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Alcohols

Building Bridges to Knowledge

Photo of a stream in near Salt Lake City, Utah Photo taken by Michaelle Cadet

Methanol, CH3OH is produced primarily from the catalytic reduction of carbon monoxide.

Methanol, a colorless liquid, is the precursor for formaldehyde and tert-butyl methyl ether. Methanol has a boiling point of 65oC and dissolves in water due to its ability to hydrogen bond. Methanol is

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unsuitable for drinking.

Ethanol, CH3CH2OH, on the other hand, can be imbibed, and it can be prepared by enzymatic fermentation. Also, ethanol can be synthesized by the hydration of ethene.

Isopropyl Alcohol, (CH3)2CHOH

Isopropyl alcohol, rubbing alcohol, is synthesized from propene.

Preparation of Alcohols

Grignard Reagents

As mentioned in the paper titled “Organometallic Compounds, Building Bridges to Knowledge, Grignard reagents can be used to prepare primary, secondary, and tertiary alcohols. Following is a review of the formation of primary, secondary, and tertiary alcohols using Grignard reagents.

Primary alcohols are synthesized from Grignard reagents and formaldehyde. For example, cyclohexylcarbinol and 2-cyclopentylethanol can be synthesized using formaldehyde as illustrated in the following reaction schema.

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cyclohexylcarbinol

l

cyclopentylethanol

Secondary alcohols are synthesized from Grignard reagents and aldehydes.

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For example, 1-cyclohexyl-1-propanol can be synthesized using propanal as illustrated in the following reaction schema.

1-cyclohexyl-1-propanol

Tertiary alcohols are synthesized from the Grignard reagents and ketones.

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For example, 1-ethylcyclohexanol can be synthesized using cyclohexanone and ethyl magnesium iodide as illustrated in the following reactions:

Tertiary alcohols (where two of the alkyl groups are the same) can be synthesized using Grignard reagents and esters.

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For example, 3-cyclohexyl-3-pentanol can be synthesized from ethyl cyclohexylcarboxylate and ethyl magnesium bromide as illustrated in the following reaction schema.

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3-cyclohexyl-3-pentanol

Reduction of Aldehydes

Primary alcohols can be produced by the catalytic reduction of aldehydes. The metal catalysts used to reduce aldehydes to ketones can be platinum, palladium, nickel, ruthenium, and other transition metals.

Following are examples of the reduction of aldehydes to form

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primary alcohols.

Cyclohexylmethanal can undergo reduction to form cyclohexylmethanol.

NaBH4, sodium borohydride, can be used in an aqueous or alcoholic medium; therefore, it is easier to handle than lithium aluminum hydride, LiAlH4. Lithium aluminum hydride reacts violently with water and alcohol; therefore, it must be used in an aprotic solvent, i.e., a solvent that doesn’t have a proton attached to an electronegative atom such as oxygen, like diethyl ether or tetrahydrofuran.

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Reduction of Ketones

Secondary alcohols can be prepared by the reduction of ketones.

For example, dicyclohexyl ketone will undergo reduction with various reagents to form dicyclohexylmethanol.

or

The reduction of dicyclohexyl ketone to dicyclohexylmethanol with

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sodium borohydride, NaBH4, involves several steps. Following are steps that could rationalize the reduction of dicyclohexyl ketone to dicyclohexylmethanol using sodium borohydride in water. The sum of the steps of the mechanism gives the reactants and products with their appropriate stoichiometric quantities.

The reduction can be illustrated by the following equation.

The mechanism of the reaction can be explained by the following set of chemical equations.

(1) The first step of the mechanism is the formation of dicyclohexylmethoxyborohydride.

(2) The second step of the mechanism is the formation of

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didicyclohexylmethoxyborate.

(3) The third step of the proposed mechanism is the formation of tridicyclohexylmethoxyborate.

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(4) The fourth step of the mechanism is the formation of tetradicyclohexylmethoxyborate.

(5) The fifth step of the mechanism is the reaction of water with tetradicyclohexylmethoxyborate to form dicyclohexylmethanol and tridicyclohexylmethoxyhydroxyborate anion.

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(6) The sixth step of the mechanism is the reaction of water with tridicyclohexylmethoxyhydroxyborate anion to form dicyclohexylmethanol and didicyclohexylmethoxydihydroxyborate anion.

(7) The seventh step of the mechanism is the reaction of water with didicyclohexylmethoxydihydroxyborate anion to form dicyclohexylmethanol and dicyclohexylmethoxytrihydroxyborate anion.

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(8) The final step, the eighth step of the mechanism, is the reaction of water with dicyclohexylmethoxytrihydroxyborate anion to form dicyclohexylmethanol and tetrahydroxyborate anion.

The sum of the eight steps of this mechanism gives the products and the reactants with their stoichiometric quantities.

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Reduction of ketones with LiAlH4 follows a mechanism analogous to the mechanism for reduction of ketones with sodium borohydride except that the reduction and hydrolysis take place separately. For example, tetraalkoxyaluminate anion is formed first followed by stepwise hydrolysis of the tetraalkoxyaluminate anion with four (4) water molecules. For example, dicyclohexylmethanol can be produced from the reduction of dicyclohexyl ketone with lithium aluminum hydride as illustrated in the following reactions:

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Hydrolysis of alkenes

Alkenes will react with water in the presence of mineral acids to form alcohols. The reaction follows the Markovnikov’s rule,i.e., the “OH” group adds to the more alkylated carbon atom. In addition, the reaction proceeds through a carbocation mechanism.

The mechanism for the formation of this tertiary alcohol

Step 1

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Step 2

Step 3

Hydroboration Oxidation Reactions

Alkenes will react with diborane followed by treatment with hydrogen peroxide in base to produce alcohols that appear to following anti-Markovnikov’s rule. In reality, the reaction follows Markovnikov’s rule, because hydrogen is more electronegative than boron; therefore, the hydrogen atom adds to the more alkylated carbon atom. The boron adds to the lesser alkylated carbon atom. Finally, the “OH” group replaces the boron, and the reaction product formed is the apparent anti-Markovnikov’s product.

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For example, cyclopentylmethanol can be produced by treating methylenecyclopentane (methylidenecyclopentane) with diborane followed by treatment with hydrogen peroxide in base as illustrated in the following reaction.

methylenecyclopentane

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cyclopentylmethanol

As indicated, the reaction occurs in two steps. The first step is the formation of the organoborane compound.

organoborane compound

The second step is treatment of the organoborane compound with hydrogen peroxide in base to form cyclopentylmethanol.

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cyclopentylmethanol

The mechanism of oxidizing the organoborane was introduced in the paper titled “Organometallic Compounds, Building Bridges to Knowledge.” Following is a review of the mechanism.

The formation of the trialkyborane compound takes place in three steps:

Step 1

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Step 2

Step 3

The sum of steps 1-3 is

The mechanism for the oxidation of the trialkylborane with hydrogen peroxide and base follow steps (1) through (12).

(1) HOOH + -OH → HOO- + HOH

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(2)

(3)

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(4)

(5) HOOH + -OH → HOO- + HOH

(6)

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(7)

(8)

(9) HOOH + -OH → HOO- + HOH

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(10)

(11)

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(12)

Hydrolysis of Alkyl Halides via an SN2 reaction

Alcohols can be formed by the hydrolysis of a primary alkyl halide. The reaction follows a substitution nucleophilic reaction. The following reaction is an illustration of the hydrolysis of iodomethylcyclopentane to produce cyclopentylmethanol.

Primary Alcohols from the Reduction of Carboxylic Acids

Carboxylic acids are difficult to reduce; however, the powerful reducing agent lithium aluminum hydride, LiAlH4, is very effective in reducing carboxylic acids to primary alcohols. Sodium borohydride is not a sufficiently strong reducing agent to reduce carboxylic acids

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to primary alcohols.

For example, cyclohexylmethanol can be produced from the reduction of cyclohexylcarboxylic acid with lithium aluminum hydride.

cyclohexylcarboxylic acid cyclohexylmethanol

The details, including the stoichiometry of the reaction, will be discussed in a future paper.

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Primary Alcohols from the Reduction of Esters

Esters are more easily reduced than carboxylic acids; however, lithium aluminum hydride is still the reducing agent of choice for synthesizing primary alcohols from esters. Two alcohols are formed when esters are reduced to alcohols using lithium aluminum hydride.

For example, cyclohexylmethanol (I) and 1-propanol (II) can be produced by reducing n-propyl cyclohexylcarboxylate (III) with lithium aluminum hydride.

III I II

Following is a partial explanation for the reduction of esters with lithium aluminum hydride.

The first step is the formation of the aluminate complex in the absence of water. The aluminate complex is formed in four steps.

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Step 1

Step 2

Step 3

Step 4

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The sum of steps 1-4 gives the following equation:

The aluminate complex reacts with a fifth aluminium hydride to form the desired tetraalkoxyaluminate anion that originates from the alkyl group attached to the carbonyl group and the tetraalkoxyaluminate anion attached to the oxygen of the ester.

(5)

The second part of the synthesis is the hydrolysis of the two tetraalkoxyaluminate anions to produce the two desired alcohols from the treatment of esters with lithium aluminum hydride. These

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results are represented by the following equation.

Reaction of Grignard Reagents with Ethylene oxide

Grignard reagents react with ethylene oxide to form primary alcohols that extend the carbon backbone by two carbon atoms.

Following is an illustration of this reaction where bromobenzene can be converted into 2-phenylethanol using ethylene oxide.

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bromobenzene

2-phenylethanol

Organolithium reagents, RLi, will also react with ethylene oxide in an analogous manner as Grignard reagents react with ethylene oxide.

Following is the mechanism for a Grignard reagent reacting with

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ethylene oxide.

Preparation of Diols

Reduction of dials via catalytic hydrogenation, lithium aluminum hydride, or sodium borohydride leads to the formation of diols.

For example, 1,6-hexanediol can be prepared from 1,6-hexanedial using catalytic hydrogenation or sodium borohydride or lithium aluminum hydride.

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Vicinal-diols

As discussed in the paper titled “Alkenes, Building Bridges to Knowledge,” vicinal (vic) diols can be prepared from alkenes via OsO4, dilute KMnO4, or peroxy acids. OsO4 and dilute KMnO4 lead to the formation of cis diols (a syn addition product), and peroxy acids lead to the formation of trans diols (an anti addition product).

A review of those reactions is helpful in reinforcing the idea that the osmate ester and the permanganate ester lead to the formation of the cis glycol. Whereas, the hydrolysis of the epoxide would lead to the formation of the trans glycol.

First, let’s review the formation of cis-glycols from the osmate ester.

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The osmate ester is formed by reacting an alkene, e.g., cyclohexene with osmium tetroxide.

The stable osmate ester can be cleaved with tert-butyl hydroperxide in a basic medium as well other reagents like hydrogen sulfide.

The reaction mechanism can be explained by the following steps.

(1) Formation of the cyclic osmate ester

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The stable osmate ester can be cleaved with tert-butyl hydroperoxide.

(1) Formation of (CH3)3COO- would have to occur twice in order to account for the stoichiometry of the reaction since two moles of (CH3)3COOH are required to balance the equation.

(2)

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(3)

(4)

(5)

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(6)

(7)

(8)

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Cis-glycols can also be formed from treating an alkene, e.g., cyclohexene, with dilute potassium permanganate.

As indicated in the paper titled “Alkenes, Building Bridges to Knowledge,” the following steps can represent the mechanism for this reaction.

(1)

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(2)

(3)

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(4)

(5)

(6)

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(7)

(8)

(9)

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(10)

(11)

(12)

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(13)

(14)

The hydrolysis of epoxides results in the formation of trans glycols.

(1)

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(2)

(3)

Formation of Intermolecular and Intramolecular Ethers from Primary Alcohols

The intermolecular and intramolecular formation of ethers using primary alcohols may be accomplished with a mineral acid.

Following are the series of elementary steps for the formation of ethers from primary alcohols.

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(1)

(2)

(3)

Diols in which the OH groups are on continuous carbon atoms that are 1,4 or 1,5 to each other can form intramolecular ethers.

The mechanism of the reaction can be visualized by the following

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three steps.

(1)

(2)

(3)

Esters can be formed from Alcohols and carboxylic acid by a reaction referred to as the Fischer Esterification reaction.

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For example, cyclopentyl cyclohexanecarboxylate can be formed by reacting cyclopentanol with cyclohexanecarboylic acid in the presence of a mineral acid.

The mechanism of the reaction can be explained by the following steps:

(1)

(2)

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(3)

(4)

(5)

(6)

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Esters can also be prepared using acyl halides and acid anhydrides.

Following is the mechanism for the reaction.

The reaction can be carried out in pyridine to capture hydrogen chloride as pyridinium chloride.

(1)

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(2)

Esters can be prepared from anhydrides . The following general reaction illustrates the reaction of an alcohol with phthalic anhydride

phthalic anhydride

Inorganic Esters

Alkyl nitrates can be prepared by reacting alcohols with nitric acid.

The mechanism for the formation of alkyl nitrates from alcohols and

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nitric acid can be explained by the following two steps.

(1)

(2)

Following is an illustration of the reaction of alcohols with nitric acid.

Formation of Dialkyl Sulfates

Dialkyl sulfates can be prepared by reacting alcohols with sulfuric acid.

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The mechanism for the formation of dialkyl sulfates from alcohols and sulfuric acid can be explained by the following steps.

(1)

(2)

(3)

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(4)

Formation of trialkyl phosphites

Trialkyl phosphites can be prepared by reacting alcohols with phosphorous acid.

The mechanism for the formation of trialkyl phosphites from alcohols and phosphorous acid can be explained by the following steps.

(1)

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(2)

(3)

(4)

(5)

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(6)

Formation of trialkyl phospates

Trialkyl phosphates can be prepared by reacting alcohols with phosphoric acid.

The mechanism for the formation of trialkyl phosphates from alcohols and phosphoric acid follows the similar mechanism as the mechanism for the reaction of H3PO3 with alcohols. Take a moment, and suggest a series of elementary steps (the mechanism) that would account for the formation of trialkyl phosphates from alcohols and phosphoric acid.

Oxidation of Primary and Secondary Alcohols

Primary Alcohols can be oxidized to carboxylic acids and secondary alcohols can be oxidized to ketones.

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For example, 1-pentanol can be oxidized to valeric acid (pentanoic acid) with potassium dichromate.

The oxidation of 1-butanol to butanoic acid using potassium dichromate was balanced using the following technique.

(1) Reduction

(2) Oxidation

14 H(aq)+ + Cr2O7 (aq)

2− + 6 −1e0 →

2 Cr (aq)3+ + 7 H2O (l)

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The electrons lost and electrons gained must balance. This can be accomplished by multiplying equation (2) by 2:

Adding equations (1) and (2) gives:

The following equation is the molecular form of the net ionic equation.

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Other oxidizing agents that may be used are chromic acid; and if one desires to stop at an aldehyde rather than the carboxylic acid, pyridinium chlorochromate (PCC) in dicloromethane or pyridinium dichromate (PDC) in dichloromethane are excellent reagents for converting primary alcohols to aldehydes.

or

Hydrocarbon attachments to an aromatic nucleus containing a primary alcohol group must be carefully oxidized to the carboxylic acids; otherwise, the entire side chain could be oxidized to benzoic acid or a benzoic acid derivative. For example, 3-phenyl-1-propanol reacts with potassium dichromate in sulfuric acid to form benzoic

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acid as the major product.

The balance molecular equation of the side chain oxidation reaction of 3-phenyl-1-propanol with potassium dichromate in sulfuric acid can be represented by the following equation.

Benzoic acid will also be formed as the primary product when 3-phenyl-1-propanol reacts with hot potassium permanganate in sulfuric acid.

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The balance molecular equation of the side chain oxidation reaction of 3-phenyl-1-propanol with potassium permanganate in sulfuric acid can be represented by the following equation.

The oxidation of side chains attached to the aromatic nucleus is probably more complicated than indicated in the previous discussion; however, for clarification purposes, let’s assume that the carbon atoms (with at least one hydrogen atom attached to them) attached to the aromatic ring will undergo complete combustion to carbon dioxide and water.

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The integrity of the side chain on the aromatic ring could be maintained in the oxidation of 3-phenyl-1-propanol if the oxidation process occurred with milder oxidation reagents. Oxidizing 3-phenyl-1-propanol in chromium (IV) oxide in sulfuric acid (the Jones reagent) would maintain the integrity of the carbon skeleton attached to the aromatic nucleus.

The balance molecular equation of the oxidation reaction of 3-phenyl-1-propanol with the Jones Reagent (CrO3/H2SO4) can be represented by the following equation.

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Ketones from Secondary Alcohols

Ketones can be prepared by treating secondary alcohols with a variety of oxidizing agents such as potassium dichromate in sulfuric acid, or potassium permanganate in sulfuric acid or pyridinium dichomate, or chromic acid. The following balanced equations are examples of formation of ketones from secondary alcohols.

Dichromate Oxidation

or

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Pyridinium Dichomate Oxidation

Chromic Acid Oxidation

The following three elementary steps rationalize the formation of cyclohexanone from cyclohexanol and chromic acid.

(1)

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(2)

(3)

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(4)

Biological Oxidation of Ethanol

Ethyl alcohol (ethanol) can be oxidized in the liver to acetaldehyde by an enzymatic (alcohol dehydrogenase) oxidative process in the presence of the coenzyme nicotinamide adenine dinucleotide, NAD.

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Notice the direction of the arrows in this enzyme catalyzed oxidation reaction. Unlike invitro processes, invivo processes may involve the release of chemical entities that would not be possible under normal laboratory conditions. For example, in the biological oxidation of ethanol, a hydride ion migrates enzymatically to nicotinamide adenine dinucleotide. This is a demonstration of the powerful impacts of enzymes (biological catalyst) on biological systems.

Cleavage of Vicinal Diols

Vic diols can be cleaved by periodic acid to produce aldehydes and ketones.

The following two steps explain the cleavage of diols with periodic acid.

(1)

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(2)

Thiols

Compounds containing the “SH” group are named as thiols or mercapto or sulfanyl compounds. For example, the nomenclature of CH3CH2CH2CH2SH is 1-butanethiol. The name of HSCH2CH2OH is 2-mercapotoethanol or 2-sulfanylethanol.

Low molecular weight thiols exhibit pungent odors. Natural gas doesn’t have an odor; therefore, in order to detect leakage of natural gases, low molecular mass alkanethiols are added to natural gas. The olfactory nerves can detect one part of ethanethiol in ten billion parts of air.

The pungent odor of thiols decreases with increasing carbon chains. L-Cysteine is a hydrophilic sulfur-containing amino acid with a mercapto or thio group on the β carbon atom. L-Cysteine can be biosynthesized in humans, and it is biologically important for the synthesis of cystine, an important amino acid used in building protein structure.

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cisteine

P-1-menthene-8-thiol contributes to the odor and taste of grapefruit.

p-1-menthene-8-thiol

The S-H bond is less polar than the O-H bond; therefore, RSH molecules don’t molecularly associate.

RSH (pKa ≈ 11) are stronger acids than ROH (pK

a ≈ 16-18).

Consequently, thiols dissolve in NaOH to form water and sodium alkanethiolates.

RSH + NaOH → RS- Na+ + H2O

RS- are weaker bases than RO- -. RS- undergoes SN2 with primary

and secondary alkyl halides.

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Problems

Alcohols

1. Arrange the following compounds in order of increasing boiling points.

(a) n-pentanol

(b) 2-methyl-2-butanol

(c) 3-methyl-2-butanol

(d) 2,2-dimethylpropanol

2. Predict the products expected when 2-methyl-1-butanol reacts with:

(a) Phosphorous and iodine

(b) Ethyl magnesium bromide

(c) tosyl chloride in HCl

(d) chromic acid

(e) sulfuric acid/heat

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3. Suggest syntheses for the following from 1-butanol and any other necessary inorganic or organic materials.

(a) n-octane

(b) trans-3-octene

(c) cis-3-octene

(d) 1,2-butanol

(e) ethylcyclopropane

(f) butanoic acid

(g) 1-butyne

(h) butanal

(i) 1-iodobutane

4. Suggest a synthesis for the following from the indicated starting material and any other necessary inorganic reagent.

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5. Suggest a synthesis for the following from the indicated starting material and any necessary inorganic material.

6. Give a rationale for the following reaction.

7. A monoterpenoid found in some essential oils (e.g., rose oil) follows the isoprene rule and exhibits the following 13C NMR spectrum. The infrared spectrum of the monoterpentoid exhibits a strong transmittance band at 3333 cm-1.

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Ozonolysis of the monterpenoid produces the following three compounds.

Suggest a structure for this monoterpenoid that is consistent with the observed data.

8. An important biological material with the molecular formula C21H40O can be synthesized by treating 1-hexyne with sodium amide, followed by treating the resulting product with 1- chloro-3-iodopropane, followed by treating the resulting product with magnesium in dry ether, followed by treating the resulting product with n-dodecanal, followed by acid hydrolysis. The product of this final reaction is reacted with hydrogen/Pd/PbO CaCO3. The resulting product is oxidized to C21H40O. Suggest a

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structure for C21H40O.

9. Suggest products for the following reactions.

(a)

(b)

(c)

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(d)

10. Suggest a synthesis for the following compound from the indicated starting materials and any other necessary organic and inorganic materials.

11. Suggest a structure for

from the following sequence of reactions.

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12. Suggest a synthesis for the following molecule from the given starting material and any other necessary organic or inorganic materials.

13. Suggest syntheses for the following molecules from 1-butanol as the only source of organic compound and any necessary inorganic materials.

(a) n-butyl mercaptan

(b) 4-octanol

(c)

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(d)

14. Suggest a synthesis for the following molecule from the indicated starting material and any other necessary inorganic material.

15. Suggest a mechanism for the following conversion.