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• Practice writing mechanisms and “talking” yourself through the steps.

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• Work as many problems as you can.

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• A free tutoring service is available through the LRC.

Spring 2011 Dr. HalliganCHM 236

• Reactions of Alcohols, Ethers, Epoxides, Amines, and Sulfur-Containing Compounds

Chapter 10

Ch. 10 Overview

• Conversion of Alcohols to Alkyl Halides and Sulfonate Esters• Substitution reactions of activated alcohols (ROH with better LG’s)• Dehydration of alcohols via Elimination Reactions• Oxidation of Alcohols• Nucleophilic Substitution Reactions of Ethers

• Nucleophilic Substitution Reactions of Epoxides• Amines Do Not Undergo Substitution or Elimination Reactions• Quaternary Ammonium Hydroxiudes Undergo Elimination

Reactions• Phase-Transfer Catalysts• Thiols, Sulfides, and Sulfonium Salts

Substitution Reactions of Alcohols

• The OH group of an alcohol is a terrible LG. Why?

• We must convert the OH group to a better LG before doing a substitution reaction.

• In this chapter, we will use HCl, HBr, HI, ZnCl2, PBr2, SOCl2, and R’SO2Cl/py to convert OH to a better LG.

OH + BrBr + OH

strong base

(you need a weak/stable base)

6

Convert the strongly basic leaving group (OH–) into the good leaving group, H2O (a weaker base):

Only weakly basic nucleophiles can be used

Alcohols and ethers have to be activated before they can undergo a substitution or an elimination reaction:

7

Primary, secondary, and tertiary alcohols all undergonucleophilic substitution reactions with HI, HBr, and HCl:

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Secondary and tertiary alcohols undergo SN1 reactions with hydrogen halides:

9

Primary alcohols undergo SN2 reactions with hydrogen halides:

Reaction carried out in 48% aqueous HBr. Recall that Br– is an excellent nucleophile in water.

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ZnCl2 can be used to catalyze certain SN2 reactions:

ZnCl2 functions as a Lewis acid that complexes strongly with the lone-pair electrons on oxygen:

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The Lucas ReagentAnhydrous ZnCl2 in conc HCl

Distinguishes primary, secondary, and tertiary low-molecular-weight alcoholsThe Lucas reaction:

ROH + HClZnCl2

RCl

Positive test: Solution becomes cloudy

Test results and mechanisms at room temperature:• Primary: No reaction• Secondary: Reaction in ~5 minutes• Tertiary, allylic, and benzylic: Reaction immediate

SN2

SN1

SN2 and SN1

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Look out for rearrangement product in the SN1 reactionof the secondary or tertiary alcohol:

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Other Methods for Converting Alcohols into Alkyl Halides

Utilization of phosphorus tribromide:

Other phosphorus reagents can be used:

PBr3, phosphorus tribromidePCl3, phosphorus trichloridePCl5, phosphorus pentachloridePOCl3, phosphorus oxychloride

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Activation by SOCl2

Pyridine is generally used as a solvent and also acts as a base:

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The Artificial Sweetener Splenda (Sucralose)

Could Splenda be a cellular alkylating agent?

No, it is too polar to enter a cell.

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Summary: Converting of Alcohols to Alkyl Halides

Recommended procedures:

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Converting Alcohols into Sulfonate Esters

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Several sulfonyl chlorides are available to activate OH groups:

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Dehydration of Secondary and Tertiary Alcohols by an E1 Pathway

To prevent the rehydration of the alkene product, one needs to remove the product as it is formed

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The major product is the most stable alkene product:

The most stable alkene product has the most stable transition state

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The rate of dehydration reflects the ease with which thecarbocation is formed:

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Look out for carbocation rearrangement:

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Complex Alcohol Rearrangements in Strong Acid

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Pinacol RearrangementProtonate alcohol: Eliminate water:

Rearrange carbocation: Deprotonate:

Resonance-stabilizedoxocarbocation

H3CO

CH3

H3C CH3

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Ring Expansion and Contraction

Show the mechanism for this reaction:

•Protonate the alcohol.•Eliminate water.•Rearrange carbocation to afford the more stable cyclohexane ring.

•Deprotonate.

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Primary Alcohols Undergo Dehydration by an E2 Pathway

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The Stereochemical Outcome of the E1 Dehydration

Alcohols and ethers undergo SN1/E1 reactions unless they would have to form a primary carbocation

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A Milder Way to Dehydrate an Alcohol

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Oxidation by Chromium (VI)

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Primary alcohols are oxidized to aldehydes and eventually carboxylic acids:

Mechanism:

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The oxidation of aldehydes to acids requires the presence of water:

In the absence of water, the oxidation stops at the aldehyde:

PCC, a methylene chloride–soluble reagent:

No water present

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A tertiary alcohol cannot be oxidized and is converted to a stable chromate ester instead:

Di-tert-Butyl ChromateNo hydrogen on this carbon

Cr

O

O

OO

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Amines do not undergo substitution reactions becauseNH2

– is a very strong base (a very poor leaving group):

Protonation of the amine moiety does not solve the problem:

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Nucleophilic Substitution Reactions of Ethers

Ethers, like alcohols, can be activated by protonation:

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Ether cleavage: an SN1 reaction:

Ether cleavage: an SN2 reaction:

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Reagents such as SOCl2 and PCl3 can activate alcohols but not ethers

Ethers are frequently used as solvents because only theyreact with hydrogen halides

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Nucleophilic Substitution Reactions of Epoxides

Recall Section 4.9

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Epoxides are more reactive than ethers in nucleophilicsubstitution reactions because of ring strain:

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Acid-Catalyzed Epoxide Ring Opening

Stereospecificity of epoxide ring opening:

A trans diol

Reason: Back-side attack of water on protonated epoxide:

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Reaction of an epoxide in the presence of methanol and acid

Mechanism:

Regioselectivity:

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When a nucleophile attacks an unprotonated epoxide, the reaction is a pure SN2 reaction:

Therefore:

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Epoxides Are Synthetically Useful Reagents

Enantiomers

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Epoxy resins are the strongest adhesives known:

Amine nucleophile mediated epoxide ring opening:

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Arene Oxides:Arene oxides are versatile compounds with interesting chemistries.

They are compounds in which one of the “double bonds” of the aromatic ring has been converted into an epoxide.

What happens to aromatic compounds when they enter the body as a foreign substance (such as cigarette smoke, drugs, charcoal-broiled meats or automobile exhaust)?

Arene Oxide Reactions• Arene oxides participate in two types of reactions.• They undergo nucleophilic attacks of the epoxide ring to form addition products

(unlike regular epoxides).• They can also undergo a rearrangement reaction to form a phenol.• Whether or not a certain arene oxide is carcinogenic depends its subsequent

reaction pathway (rearrangement or nucleophilic substitution).• If it proceeds through the rearrangement pathway, non-carcinogenic phenols will

be produced. • However, if it undergoes nucleophilic attack by DNA, this can lead to carcinogenic

products.

O

Y

OH

OH

addition product

rearranged product

Y

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Mechanism for arene oxide rearrangement:

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How Do Arene Oxides Cause Cancer?

DNAbackbone

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BENZO[a]PYRENE EPOXIDATION

Not all smokersget cancer

Benzopyrenes in chimneys were responsible for cancer of the scrotum in “chimney-boys.” The connection between cancer and chimney soot was made by Percivall Pott in 1775.

Reactions of 4° Ammonium Hydroxides

• A fully alkylated amino group (quaternary), makes a good enough LG for the “E2” Hofmann Elimination Reaction.

• If the 4° amino group was protonated, the E2 base, would just deprotonate the 4° amino group and there would be no E2 reaction.

Hofmann Elimination Favors anti-Zaitsev Products

• Do you remember the 3 exceptions for E2 reactions in terms of predicting the major products?

• Usually, the more substituted alkene is the major product except if there is a big bulky base, possibility of conjugation or a Fluorine LG.

• Here, the quaternary ammonium salt is a relatively slow LG just like Fluorine. As the E2 base comes in to abstract the proton, a negative charge starts to build up on the B-carbon. Remember that carbanion stability is the opposite of carbocation stability.

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Crown Ethers

The ability of a host to bond only certain guests is an example of molecular recognition

Crown Ether Reactions

• Crown ethers serve as excellent phase-transfer catalysts for reactions.

• The crown ether enables a reaction to be carried out in two phases (polar and nonpolar).

• This is exemplified in the reaction of 1-bromohexane with acetate ion. • The acetate ion is only soluble in water whereas the 1-bromohexane is only

soluble in nonpolar solvents. • The crown ether helps dissolve the acetate by binding the inorganic ion species

(e.g. Na+ or K+) in its cavity and then the whole crown-guest complex is soluble in the nonpolar solvent (benzene in this case).

Br OK

O [18]-crown-6

O

O

+ Br+

nonpolar solvents water soluble

benzenesoluble in

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Thiols are sulfur analogs of alcohols:

Thiols are not good at hydrogen bonding

Thiols form strong complexes with heavy metal cations

Thiols are stronger acids (pKa = 10) than alcohols

Thiols, Sulfides, and Sulfonium Salts• Thiols are sulfur analogs of alcohols

with SH replacing the OH of the alcohol.

• Thiols are also known as mercaptans because they form stable heavy metal derivatives with species such as mercuric and arsenic ions.

• Low MW thiols have strong and offensive odors, such as those present in onions, garlic and skunks.

• The –SH group ranks just below an alcohol in terms of naming.

SH SHSH HS

OH

ethanethiol 1-propanethiol 3-methyl-1-butanethiol 2-mercaptoethanol

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In protic solvent, thiolate ions are better nucleophiles than alkoxide ions:

Sulfur is an excellent nucleophile because its Electron cloud is polarized