13 -1 Klein, Organic Chemistry 1e Copyright 13 -2 Klein ...

• Alcohols possess a hydroxyl group (–OH).

• Hydroxyl groups are extremely common in natural compounds.

13.1 Alcohols and Phenols

Copyright 2012 John Wiley & Sons, Inc. Klein, Organic Chemistry 1e13 -1

• Hydroxyl groups in natural compounds.



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



• Alcohols are named using the same procedure we used in Chapter 4 to name alkanes with minor modifications:1. Identify the parent chain, which should include the carbon that

the –OH is attached to.

2. Identify and name the substituents.

3. 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.

13.1 Alcohols and Phenols –Nomenclature


• Alcohols are named using the same procedure we used in Chapter 4 to name alkanes with minor modifications:1. Identify the parent chain.

2. Identify and name the substituents.



• Alcohols are named using the same procedure we used in Chapter 4 to name alkanes with minor modifications:3. 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.



• Alcohols are named using the same procedure we used in Chapter 4 to name alkanes with minor modifications:5. 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.



• 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:



• Like halides, alcohols are often classified by the type of carbon they are attached to:

• WHY do we use these classifications?



• When an –OH group is attached to a benzene ring, the parent name is PHENOL.

• Practice with SKILLBUILDER 13.1.



• Name the following molecule.

• Draw the most stable chair conformation for (cis)‐1‐isopropyl‐1,4‐cyclohexadiol



HOCl Br

• Methanol (CH3OH) is the most simple alcohol.

• With a suitable catalyst, about 2 billion gallons of methanol are made industrially from CO2 and H2 every year.

• Methanol is quite poisonous, but it has many uses as:1. Solvent

2. Precursor for chemical syntheses

3. Fuel

13.1 Alcohols and Phenols –Commercially Important Alcohols


• Ethanol (CH3CH2OH) has been produced by fermentation for thousands of years. HOW?

• About 5 billion gallons of ethanol are made industrially from the acid‐catalyzed hydration of ethylene every year.

• Ethanol has many uses as:1. Solvent, precursor for chemical syntheses, fuel

2. Human consumption —ethanol suitable for drinking is heavily taxed. If you want to use ethanol for other purposes, how do you avoid the tax?

• Is it poisonous?



• 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 as:1. Industrial solvent

2. Antiseptic

3. Gasoline additive



• The –OH of an alcohol can have a big effect on its physical properties.

• Compare the boiling points below.

• Explain the differences.

13.1 Alcohols and Phenols – Physical Properties of Alcohols


• Because they can hydrogen‐ (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.



• Do HYDROPHOBIC groups repel or attract water?

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

• Alcohols with three or less carbons are generally water miscible.

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



• The potency as an anti‐bacterial agent for an alcohol 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 why solvation is a stabilizing effect.




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



• 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 CONCEPTUAL 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 states 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 Preparation of Alcohols 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?




• 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 know:1. 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 groups

– Sterically hindered groups



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



• To reduce an ester, two hydride equivalents are needed.– Which steps in the mechanism are reversible?



• Predict the products for the following processes.




• 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 collides 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 five carbons or less.



• 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 PBr3mechanisms are SN2 reactions.




• Fill in the necessary reagents for the conversions below.



• 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 Reactions of Alcohols –E1 and E2


• 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.


13.9 Reactions of Alcohols –E1 and E2


• 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 proceeds to aldehydes and subsequently to carboxylic acids

– 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 is generally used with methylene chloride as the solvent.

• Both oxidizing agents will work with secondary alcohols.




• Predict the product for the following reaction.



• 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 a big 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 ubiquinones 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:





• Give necessary reagents for the following conversions.




• Recall the C‐C bond forming reactions we learned.



• 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.



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