Organic Chemistry Chapter 12 Alcohols

Chapter 12 Alcohols

Waterway Michaelle Cadet

“Nature composes some of her loveliest poems for the microscope and the telescope.�

Theodore Roszak, Where the Wasteland Ends: Politics and Transcendence in Post-Industrial Society

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The primary synthesis of methanol, CH3OH, is the catalytic reduction of carbon monoxide.

Methanol, a colorless liquid, is a 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. Unlike ethanol, methanol is unsuitable for drinking.

Ethanol, CH3CH2OH, on the other hand, is suitable for drinking (in moderation) and synthesized by enzymatic fermentation. The hydration of ethene is another method for synthesizing ethanol.

Propene is a precursor for synthesizing Isopropyl Alcohol, (CH3)2CHOH or rubbing alcohol.

Preparation of Alcohols Grignard Reagents Grignard reagents can be used to prepare primary, secondary, and tertiary alcohols.

The following is a review of the formation of primary, secondary, and tertiary alcohols using Grignard reagents.

Grignard reagents and formaldehyde are precursors for synthesizing primary alcohols.

For example, formaldehyde is a precursor for synthesizing cyclohexylcarbinol and 2cyclopentylethanol.

The following schemas illustrate these syntheses:

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cyclohexylcarbinol

l

Cyclopentylethanol

Grignard reagents and aldehydes are precursors for the syntheses of secondary alcohols.

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For example, The following schema illustrates the synthesis of 1-cyclohexyl-1-propanol from propanal:

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1-cyclohexyl-1-propanol

Grignard reagents and ketones are precursors to the syntheses of tertiary alcohols.

For example, cyclohexanone and ethyl magnesium iodide are precursors for the synthesis of 1-ethylcyclohexanol.

The following illustrates this synthesis:

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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, ethyl cyclohexylcarboxylate and ethyl magnesium bromide are precursors for the synthesis of 3-cyclohexyl-3-pentanol as illustrated in the following reaction schema:

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3-cyclohexyl-3-pentanol

Reduction of Aldehydes The catalytic reduction of aldehydes lead to the production of primary alcohols. Metal catalysts that will reduce aldehydes to ketones are platinum, palladium, nickel, ruthenium, and other transition metals.

The following are examples of the reduction of aldehydes to primary alcohols: Cyclohexylmethanal can undergo reduction to form cyclohexylmethanol.

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NaBH4, sodium borohydride, in an aqueous or alcoholic medium, will reduce aldehydes to primary alcohols. Also, lithium aluminum hydride will reduce aldehydes to alcohols.

However, sodium borohydride is easier to handle than lithium aluminum hydride, LiAlH4. Lithium aluminum hydride reacts violently with water and alcohol; therefore, the solvents used for reductions with LiAlH4 must be aprotic (solvents that do not have protons attached to electronegative atoms such as oxygen, e.g., diethyl ether or tetrahydrofuran).

Reduction of Ketones The reduction of ketones lead to secondary alcohols.

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

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dicyclohexyl ketone

dicyclohexylmethanol

or

The reduction of dicyclohexyl ketone to dicyclohexylmethanol with sodium borohydride, NaBH4, involves seven steps.

The following eight (8) steps rationalize the reduction of dicyclohexyl ketone to dicyclohexylmethanol with sodium borohydride in water: (1) The first step of the mechanism is the formation of dicyclohexylmethoxyborohydride.

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(2)

The second step of the mechanism is the formation of

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 tridicyclohexylmethoxyhydoxyborate anion to form dicyclohexylmethanol and didicyclohexylmethoxydihydoxyborate anion.

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

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

The sum of the eight steps for this mechanism gives the products (the alcohol and tetrahydroxyborate) and the reactants (dicyclohexyl ketone and borohydride) with their stoichiometric quantities.

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The following is the equation in its molecular form.

The reduction of ketones with LiAlH4 follows a mechanism analogous to the mechanism for the reduction of ketones with sodium borohydride except that the reduction and hydrolysis take place separately.

The tetraalkoxyaluminate anion forms first followed by the stepwise hydrolysis of the tetraalkoxyaluminate anion with four (4) water molecules.

For example, dicyclohexylmethanol forms from the reduction of dicyclohexyl ketone with lithium aluminum hydride as illustrated in the following reaction:

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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 follow 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, treating methylenecyclopentane (methylidenecyclopentane) with diborane followed by treatment with hydrogen peroxide in base will produce cyclohexylmethanol as illustrated in the following reaction:

methylenecyclopentane

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cyclohexylmethanol

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 cyclohexylmethanol.

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cyclohexylmethanol

Chapter 3 introduced the mechanism of oxidizing the organoborane The 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).

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(1) HOOH + -OH → HOO- + HOH (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)

(12)

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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 to alcohols.

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

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cyclohexylcarboxylic acid

cyclohexylmethanol

Chapter 16 discusses the details of this reaction including the mechanism that leads to the stoichiometry of the products and the reactants..

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, the reduction of n-propyl cyclohexylcarboxylate with lithium aluminum hydride leads to formation of cyclohexylmethanol and 1-propanol.

n-propyl cyclohexylcarboxylate

cyclohexylmethanol

1-propanol

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

Steps 1-4 represent the formation of the aluminate complex in the absence of water.

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.

(5)

The second part of the synthesis is the hydrolysis of the two tetraalkoxyaluminate anions.

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Reaction of Grignard Reagents with Ethylene oxide Grignard reagents react with ethylene oxide to form primary alcohols that extends the carbon backbone by two carbon atoms.

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

bromobenzene

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2-phenylethanol

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

The following is the mechanism for a Grignard reagent reacting with ethylene oxide.

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

For example, the reduction of 1,6-hexanedial via catalytic hydrogenation or sodium borohydride or lithium aluminum hydride will lead to the formation of 1,6-hexanediol.

Vicinal-diols As discussed in Chapter 3, 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).

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A review of those reactions helps reinforce 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. 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.

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Formation of the cyclic osmate ester

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)

(6)

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(7)

(8)

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

As indicated in Chapter 3, the following elementary steps represent the mechanism for the formation of cis-glycols using dilute potassium permanganate:

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(1)

(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.

The 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 four carbon atoms apart or five carbon atoms apart can form intramolecular ethers.

The mechanism of the reaction can be visualized by the following three steps.

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(1)

(2)

(3)

Alcohols and carboxylic acid are precursors for the syntheses of esters. The reaction is the Fischer Esterification reaction.

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For example, reacting cyclopentanol with cyclohexanecarboylic acid in the presence of a mineral acid will produce cyclopentyl cyclohexanecarboxylate.

The mechanism of the reaction can be explained by the following five steps.

(1)

(2)

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(3)

(4)

(5)

(6)

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Acyl Halides are precursors for esters.

Following is the mechanism for the reaction.

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

(1)

(2)

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Acid anhydrides are precursors for esters.

The following eaction illustrates the reaction of an alcohol with phthalic anhydride

phthalic anhydride

Inorganic Esters The reaction between alcohols with nitric acid leads to alkyl nitrates.

The following is the mechanism for the formation of alkyl nitrates from alcohols and nitric acid: (1)

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(2)

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

Formation of Dialkyl Sulfates Reacting alcohols with sulfuric acid leads to the formation of dialkyl sulfates.

The following is a mechanism for the formation of dialkyl sulfates from alcohols and sulfuric acid:.

(1)

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(2)

(3)

(4)

Formation of trialkyl phosphites Reacting alcohols with phosphorous acid leads to the formation of trialkyl phosphites.

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The following mechanism rationalizes the formation of trialkyl phosphites from alcohols and phosphorous acid six: (1)

(2)

(3)

(4)

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(5)

(6)

Formation of trialkyl phosphates Reacting alcohols with phosphoric acid leads to the formation of trialkyl phosphates.

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

Oxidation of Primary and Secondary Alcohols The oxidation of primary Alcohols leads to carboxylic acids, and the oxidation of

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secondary alcohols leads to ketones.

For example, treating 1-pentanol with potassium dichromate leads to valeric acid (pentanoic acid.

(1) Reduction

or

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(2) Oxidation

The electrons lost and electrons gained must balance. Therefore, multiply the oxidation half-reaction, equation 2, by 3:

Adding equations (1) and (2) gives

or

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

Other oxidizing agents 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 56

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

The following equation represents the balance molecular equation of the side chain oxidation reaction of 3-phenyl-1-propanol with potassium dichromate in sulfuric acid:

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

The following equation represents the balance molecular equation of the side chain oxidation reaction of 3-phenyl-1-propanol with potassium permanganate in sulfuric acid:

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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.

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 following equation represents the balance molecular equation of the oxidation reaction of 3-phenyl-1-propanol with the Jones Reagent (CrO3/H2SO4).

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Ketones from Secondary Alcohols Treating secondary alcohols with a variety of oxidizing agents such as potassium dichromate in sulfuric acid, or potassium permanganate in sulfuric acid or pyridinium dichromate, or chromic acid will result in the formation of ketones.

The following balanced equations are examples of formation of ketones from secondary alcohols.

Dichromate Oxidation

or

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Pyridinium Dichromate Oxidation

Chromic Acid Oxidation

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The following three elementary steps rationalizes the formation of cyclohexanone from the reaction of cyclohexanol with chromic acid: (1)

(2)

(3)

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(4)

Biological Oxidation of Ethanol Oxidation of ethyl alcohol (ethanol) to acetaldehyde (catalyzed by alcohol dehydrogenase) occurs in the liver. The oxidative process occurs 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 Periodic acid cleaves vic-diols to produce aldehydes and ketones.

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

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(1)

(2)

Thiols Compounds containing the “SH” group are thiols or mercaptos or sulfanyls. 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, to detect leakage of natural gases, gas companies add low molecular mass alkanethiols to natural gas. The olfactory nerves can detect one part of ethanediol 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. The body can naturally synthesize L-Cysteine, and it is biologically important for the synthesis of L-cystine, an important amino acid used in building protein structure.

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cisteine

There are other naturally occurring thios in nature that do not have pungent odors. For example, 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, unlike ROH, don’t molecularly associate.

RSH (pKa ≈ 11) are stronger acids than ROH (pKa ≈ 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 1.

Arrange the following compounds in order of increasing boiling points. 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: Phosphorous and iodine Ethyl magnesium bromide tosyl chloride in HCl chromic acid sulfuric acid/heat 3.

Suggest syntheses for the following from 1-butanol and any other necessary inorganic or organic materials. n-octane trans-3-octene cis-3-octene 1,2-butanol ethylcyclopropane

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butanoic acid 1-butyne butanal 1-iodobutane 4.

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

5.

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

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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 .

Ozonolysis of the monterpenoid produces the following three

compounds.

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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-undecanal, followed by acid hydrolysis. The hydrogen/Pd/PbO

product of this final reaction is reacted with

CaCO3. The resulting product is oxidized to C21H40O. Suggest a

structure for C21H40O. 9.

Suggest products for the following reactions. (a)

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(b)

(c)

(d)

10.

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

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11.

Suggest a structure for

from the following sequence of reactions.

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

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(c)

(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.

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Solutions to Problems Chapter 12

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 The molecule that has the most spherical structure would have the lowest boiling point, and the molecule with the most linear structure would have the highest boiling point; therefore, the boiling points would be: (a)>(c)>(b)>(d) 2.

Predict the products expected when 2-methyl-1-butanol reacts with: a. Phosphorous and iodine

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(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

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(c) cis-3-octene Use the same sequence of reactions in (b) to prepare 3-octyne, than treat 3-octyne with the Lindlar catalyst.

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(d) 1,2-butanol

(e) ethylcyclopropane

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(b) butanoic acid

(g) 1-butyne 1-butyne has been synthesized from 1-butanol in “(b).�

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(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.

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6.

Give a rationale for the following reaction.

The tosyl group is a facile leaving group, and elimination occurs in a trans configuration. The tosyl group and H2 are in the cis configuration; therefore, H2 will not be removed during the elimination process. On the other hand, H1 is trans to the tosyl group; therefore, H1 is the preferred hydrogen atom that will be removed during the elimination process.

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or

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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 monoterpenoid exhibits a strong transmittance band at 3333 cm-1 .

Ozonolysis of the monoterpenoid 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 synthesized by treating 1-hexyne with sodium

C21H40O can be

amide, followed by treating the

resulting product with 1- chloro-3-iodopropane, followed by treating the resulting

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product with magnesium in dry ether, followed by treating the resulting product with ndodecanal, 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 structure for C21H40O. (1)

(2)

(3)

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(4)

(5)

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(6)

9.

Suggest products for the following reactions. (a)

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(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.

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11.

Suggest a structure for

12.

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

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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 Prepare the appropriate alkyl halide from 1-butanol.

Prepare the appropriate Grignard reagent from the alkyl halide.

Prepare butanal from 1-butanol.

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React the Grignard reagent with butanal.

(c)

4-Octanone, (c), can be prepared by the oxidation of the product of (b) , 4-octanol.

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(d)

Prepare 2-butanone from 1-butanol using the following sequence of reactions:

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React the Grignard reagent with 2-butanone

14.

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

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15.

Suggest a mechanism for the following conversion.

(1)

(2)

(3)

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(4)

(5)

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