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Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

Chapter 13Alcohols and Phenols

Organic ChemistrySecond Edition

David Klein

13.1 Alcohols and Phenols• Alcohols possess a hydroxyl group (-OH)

• Hydroxyl groups are extremely common in natural compounds

Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. 13-2 Klein, Organic Chemistry 2e

13.1 Alcohols and Phenols• Hydroxyl groups in natural compounds


• Phenols possess a hydroxyl group directly attached to an aromatic ring

13.1 Alcohols and Phenols


13.1 Alcohols Nomenclature• Alcohols are named using the same procedure we used

in Chapter 4 to name alkanes with minor modifications1. Identify the parent chain, which should include the carbon

that the –OH is attached to2. Identify and Name the substituents3. Assign a locant (and prefix if necessary) to each substituent.

Give the carbon that the –OH is attached to the lowest number possible

4. List the numbered substituents before the parent name in alphabetical order. Ignore prefixes (except iso) when ordering alphabetically

5. The –OH locant is placed either just before the parent name or just before the -ol suffix



in Chapter 4 to name alkanes with minor modifications1. Identify the parent chain



in Chapter 4 to name alkanes with minor modifications3. Assign a locant (and prefix if necessary) to each substituent.

Give the carbon that the –OH is attached to the lowest number possible taking precedence over C=C double bonds



in Chapter 4 to name alkanes with minor modifications5. The –OH locant is placed either just before the parent name

or just before the -ol suffix

• R or S configurations should be shown at the beginning of the name


13.1 Alcohols Nomenclature• For cyclic alcohols, the –OH group should be on carbon

1, so often the locant is assumed and omitted

• Common names for some alcohols are also frequently used


13.1 Alcohols Nomenclature• Like halides, alcohols are often classified by the type of

carbon they are attached to

• WHY do we use these classifications?


13.1 Alcohols Nomenclature• When an –OH group is attached to a benzene ring, the

parent name is phenol

• Practice with SkillBuilder 13.1


13.1 Alcohols Nomenclature• Name the following molecule

• Draw the most stable chair conformation for (cis)-1-isopropyl-1,2-cyclohexanediol

HOCl Br


13.1 Commercially Important Alcohols• Methanol (CH3OH) is the simplest alcohol• With a suitable catalyst, about 2 billion gallons of

methanol is made industrially from CO2 and H2 every year

• Methanol is poisonous, but it has many uses1. Solvent 2. Precursor for chemical syntheses 3. Fuel


13.1 Commercially Important Alcohols• Ethanol (CH3CH2OH) has been produced by

fermentation for thousands of years. HOW?• About 5 billion gallons of ethanol is made industrially

from the acid-catalyzed hydration of ethylene every year• Ethanol has many uses

1. Solvent, precursor for chemical syntheses, fuel2. Human consumption – ethanol suitable for drinking is heavily

taxed. Ethanol used for purposes other than drinking is often denatured. WHY?

• Is it poisonous?


13.1 Commercially Important Alcohols• Isopropanol is rubbing alcohol. Draw its structure• Isopropanol is made industrially from the acid-catalyzed

hydration of propylene• Isopropanol is poisonous, but it has many uses

1. Industrial solvent2. Antiseptic3. Gasoline additive


13.1 Physical Properties of Alcohols• The –OH of an alcohol can have a big effect on its

physical properties• Compare the boiling points below

• Explain the differences


• Because they can H-bond, hydroxyl groups can attract water molecules strongly

• Alcohols with small carbon chains are miscible in water (they mix in any ratio). WHY?

• Alcohols with large carbon chains do not readily mix with water

13.1 Physical Properties of Alcohols


• Do hydrophobic groups repel or attract water?

• WHY are molecules with large hydrophobic groups generally insoluble in water?

• Alcohols with 3 or less carbons are generally water miscible

• Alcohols with more than 3 carbons are not miscible, and their solubility decreases as the size of the hydrophobic group increases



• An alcohol’s potency as an anti-bacterial agent depends on the size of the hydrophobic group


• To kill a bacterium, the alcohol should have some water solubility. WHY?

• To kill a bacterium, the alcohol should have a significant hydrophobic region. WHY?


• Hexylresorcinol is used as an antibacterial and as an antifungal agent

• It has a good combination of hydrophobic and hydrophilic regions

– It has significant water solubility– Its nonpolar region helps it to pass through cell membranes

• Practice with conceptual checkpoint 13.3



• A strong base is usually necessary to deprotonate an alcohol

• A preferred choice to create an alkoxide is to treat the alcohol with Na, K, or Li metal. Show the mechanism for such a reaction


13.2 Acidity of Alcohols and Phenols


• Recall from chapter 3 how ARIO is used to qualitatively assess the strength of an acid

• Lets apply these factors to alcohols and phenols– Atom



• Lets apply these factors to alcohols and phenols– Resonance

– Explain why phenol is 100 million times more acidic than cyclohexanol

– Show all relevant resonance contributors



• Given the relatively low pKa of phenols, will NaOH be a strong enough base to deprotonate a phenol?



• Lets apply these factors to alcohols and phenols– Induction: unless there is an electronegative group nearby,

induction won’t be very significant

– Orbital: in what type of orbital do the alkoxide electrons reside? How does that effect acidity?



• Solvation is also an important factor that affects acidity• Water is generally used as the solvent when measuring

pKa values• Which of the alcohols below is stronger?

• ARIO cannot be used to explain the difference



• Solvation explains the difference in acidity

• Draw partial charges on the solvent molecules to show how solvation is a stabilizing effect




• Use ARIO and solvation to rank the following molecules in order of increasing pKa


HO

ON

HO

HOHO


• We saw in chapter 7 that substitution reactions can yield an alcohol

• What reagents did we use to accomplish this transformation?

• We saw that the substitution can occur by SN1 or SN2

13.3 Preparation of Alcohols


• The SN1 process generally uses a weak nucleophile (H2O), which makes the process relatively slow

• Why isn’t a stronger nucleophile (-OH) used under SN1 conditions?



• In chapter 9, we learned how to make alcohols from alkenes

• Recall that acid-catalyzed hydration proceeds through a carbocation intermediate that can possibly rearrange

• How do you avoid rearrangements?• Practice with checkpoints 13.7 and 13.8



• A third method to prepare alcohols is by the reduction of a carbonyl. What is a carbonyl?

• Reductions involve a change in oxidation state• Oxidation state are a method of electron bookkeeping• Recall how we used formal charge as a method of

electron bookkeeping – Each atom is assigned half of the electrons it is sharing with

another atom– What is the formal charge on carbon in methanol?

13.4 Alcohol Prep via Reduction


• For oxidation states, we imagine the bonds breaking heterolytically, and the electrons go to the more electronegative atom



• Each of the carbons below have zero formal charge, but they have different oxidation states

• Calculate the oxidation number for each

• Is the conversion from formic acid carbon dioxide an oxidation or a reduction?

• What about formaldehyde methanol?• Practice with SkillBuilder 13.3



• The reduction of a carbonyl requires a reducing agent

• Is the reducing agent oxidized or reduced?• If you were to design a reducing agent, what element(s)

would be necessary?• Would an acid such as HCl be an appropriate reducing

agent? WHY or WHY NOT?



• There are three reducing agents you should know1. We have already seen how catalyzed hydrogenation can

reduce alkenes. It can also work for carbonyls

– Forceful conditions (high temperature and/or high pressure)



• Reagents that can donate a hydride are generally good reducing agents

2. Sodium borohydride



• Reagents that can donate a hydride are generally good reducing agents

3. Lithium aluminum hydride (LAH)



• Note that LAH is significantly more reactive that NaBH4

• LAH reacts violently with water. WHY?

• How can LAH be used with water if it reacts with water?



• Hydride delivery agents will somewhat selectively reduce carbonyl compounds



• The reactivity of hydride delivery agents can be fine-tuned by using derivatives with varying R-groups

– Alkoxides– Cyano– Sterically hindered groups



• LAH is strong enough to also reduce esters and carboxylic acids, whereas NaBH4 is generally not



• To reduce an ester, 2 hydride equivalents are needed



• To reduce an ester, 2 hydride equivalents are needed

• Which steps in the mechanism are reversible?



• Predict the products for the following processes



O

O

O NaBH4

H2O

1) LAH

2) H3O+


• Diols are named using the same method as alcohols, except the suffix, “diol” is used

13.5 Preparation of Diols


• If two carbonyl groups are present, and enough moles of reducing agent are added, both can be reduced



• Recall the methods we discussed in chapter 9 to convert an alkene into a diol



• Grignard reagents are often used in the synthesis of alcohols

• To form a Grignard, an alkyl halide is treated with Mg metal

• How does the oxidation state of the carbon change upon forming the Grignard?

13.6 Grignard Reactions


• The electronegativity difference between C (2.5) and Mg (1.3) is great enough that the bond has significant ionic character

• The carbon atom is not able to effectively stabilize the negative charge it carries

• Will it act as an acid, base, electrophile, nucleophile, etc.?



• If the Grignard reagent reacts with a carbonyl compound, an alcohol can result

• Note the similarities between the Grignard and LAH mechanisms



• Because the Grignard is both a strong base and a strong nucleophile, care must be taken to protect it from exposure to water

• If water can’t be used as the solvent, what solvent is appropriate?

• What techniques are used to keep atmospheric moisture out of the reaction?



• Grignard examples

• With an ester substrate, excess Grignard reagent is required. WHY? Propose a mechanism

• List some functional groups that are NOT compatible with the Grignard




• Design a synthesis for the following molecules starting from an alkyl halide and a carbonyl, each having 5 carbons or less


OH

+ En

OH


• Consider the reaction below. WHY won’t it work?

• The alcohol can act as an acid, especially in the presence of reactive reagents like the Grignard reagent

• The alcohol can be protected to prevent it from reacting

13.7 Protection of Alcohols


• A three-step process is required to achieve the desired overall synthesis



• One such protecting group is trimethylsilyl (TMS)

• The TMS protection step requires the presence of a base. Propose a mechanism



• Evidence suggests that substitution at the Si atom occurs by an SN2 mechanism

• Because Si is much larger than C, it is more open to backside attack



• The TMS group can later be removed with H3O+ or F-

• TBAF is often used to supply fluoride ions






• 2 million tons of phenol is produced industrially yearly

• Acetone is a useful byproduct• Phenol is a precursor in many chemical syntheses

– Pharmaceuticals– Polymers– Adhesives– Food preservatives, etc.

13.8 Preparation of Phenols


• Recall this SN1 reaction from section 7.5

• For primary alcohols, the reaction occurs by an SN2

13.9 Reactions of Alcohols


• The SN2 reaction also occurs with ZnCl2 as the reagent

• Recall from section 7.8 that the –OH group can be converted into a better leaving groups such as a tosyl group



• SOCl2 can also be used to convert an alcohol to an alkyl chloride



• PBr3 can also be used to convert an alcohol to an alkyl bromide

• Note that the last step of the SOCl2 and PBr3 mechanisms are SN2




• Fill in the necessary reagents for the conversions below


OH OTs

OH Cl


• In section 8.9, we saw that an acid (with a non-nucleophilic conjugate base) can promote E1

• Why is E2 unlikely?• Recall that the reaction generally produces the more

substituted alkene product

13.9 E1 and E2 Reactions of Alcohols


• If the alcohol is converted into a better leaving group, then a strong base can be used to promote E2

• E2 reactions do not involve rearrangements. WHY?• When applicable, E2 reactions also produce the more

substituted product• Practice with conceptual checkpoint 13.21

13.9 E1 and E2 Reactions of Alcohols


• We saw how alcohols can be formed by the reduction of a carbonyl

• The reverse process is also possible with the right reagents

13.10 Oxidation of Alcohols


• Oxidation of primary alcohols proceed to an aldehyde and subsequently to the carboxylic acid

– Very few oxidizing reagents will stop at the aldehyde

• Oxidation of secondary alcohols produces a ketone– Very few agents are capable of oxidizing the ketone



• Tertiary alcohols generally do not undergo oxidation. WHY?

• There are two main methods to produce the most common oxidizing agent, chromic acid



• When chromic acid reacts with an alcohol, there are two main steps



• Chromic acid will generally oxidize a primary alcohol to a carboxylic acid

• PCC (pyridinium chlorochromate) can be used to stop at the aldehyde



• PCC (pyridinium chlorochromate) is generally used with methylene chloride as the solvent

• Both oxidizing agents will work with secondary alcohols


• Practice with SkillBuilder 13.7Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. 13-74 Klein, Organic Chemistry 2e

• Predict the product for the following reaction


OH

O

OH ex H2CrO4

acetone

H


• Nature employs reducing and oxidizing agents• They are generally complex and selective. WHY?• NADH is one such reducing agent

13.11 Biological Redox Reactions


• The reactive site of NADH acts as a hydride delivery agent

• This is one way natureconverts carbonyls into alcohols

• Why is an enzyme required?



• NAD+ can undergo the reverse process

• The NADH / NAD+ interconversion plays abig role in metabolism



• Recall that tertiary alcohols do not undergo oxidation, because they lack an alpha proton

• You might expect phenol to be similarly unreactive

• Yet, phenol is even more readily oxidized than primary or secondary alcohols

13.12 Oxidation of Phenol


• Phenol oxidizes to form benzoquinone, which in turn can be reduced to hydroquinone

• Quinones are found everywhere in nature• They are ubiquitous



• Ubiquinones act to catalyze the conversion of oxygen into water, a key step in cellular respiration

• Where in a cell do you think unbiquinones are most likely found?



• Ubiquinone catalysis:



• Recall some functional group conversions we learned

13.13 Synthetic Strategies


• Classify the functional groups based on oxidation state





13.13 Synthetic Strategies• Give necessary reagents for the following conversions


OBrO

HO


13.13 Synthetic Strategies• Recall the C-C bond forming reactions we learned


13.13 Synthetic Strategies• What if you want to convert an aldehyde into a ketone?

• What reagents are needed for the following conversion?

• Practice with conceptual checkpoint 13.27 and SkillBuilder 13.9

OO


Additional Practice Problems• Name the following molecule

• Draw (1R,2R)-1-(3,3-dimethylbutyl)-3,5-cyclohexadien-1,2-diol

HO


• Use ARIO and solvation to rank the following molecules in order of increasing pKa

Additional Practice Problems

OH

OH OH OHCl

Cl

Cl

A B C D


• Predict the products for the following processes


O

O O

NaBH4 / MeOH

1) LAH2) H2O

H2 / Pd

MeOH


• Design a synthesis for the following molecule starting from an alkyl halide and a carbonyl, each having 5 carbons or less


OH


• Give necessary reagents for the multi-step synthesis below


Cl

OH


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