L

TOPIC&6.&NUCLEOPHILIC&AND&RADICAL& SUBSTITUTIONS& (chapter&6&and&parts&of&chapters&10&and&11)&

OBJECTIVES&
1. &Describe&two&pathways&(mechanisms)&to&account&for&subsKtuKon&at&sp3&carbons& bearing&an&electronegaKve&atom&(leaving&group)& 2. Discuss&the&eect&of&starKng&material&(substrate),&leaving&group,&reagent&(a& nucleophile)&and&reacKon&condiKons&on&the&course&of&a&reacKon& 3. Recognize&funcKonal&group&transformaKons&and&synthesis&of&new&molecules&in& one&step&by&subsKtuKon&of&an&appropriate&material& 4. Explore&the&subsKtuKon&chemistry&of&alcohols&and&ethers& 5. Explore&the&mechanism&of&radical&subsKtuKon&

S:6.1-6.5

OVERVIEW:(( NUCLEOPHILIC(SUBSTITUTIONS(

Introduc9on(
The&polarity&of&a&carbonWhalogen&bond&leads&to&the&carbon&having&a&parKal&posiKve& charge.&&In&alkyl&halides&this&polarity&causes&the&carbon&to&become&acKvated&to& subsKtuKon&reacKons&with&nucleophiles.&

CarbonWhalogen&bonds&get&less&polar,&longer&and&weaker&in&going&from&uorine&to&iodine&

Structural(Types(of(Organic(Halides(

Nucleophilic(Subs9tu9on(Reac9ons(
In&these&types&of&reacKons&a&nucleophile&(a&species&with&an&unshared&electron&pair)& reacts&with&an&electron&decient&carbon&bearing&a&leaving(group.&&&The&leaving&group& is&displaced&by&a&nucleophile&and&separates&from&the&carbon&with&its&pair&of&electrons.&

Examples&of&nucleophilic&subsKtuKon:&

A&leaving(group(is&a&subsKtuent&that&can&leave&as&a&relaKvely&stable&enKty&with&the& pair& of& electrons& originally& bonding& it& to& carbon.& & It& can& leave& as& an& anion& or& a& neutral&species.&

We are only considering sp3 (alkyl) substrates in this section. Molecules with leaving groups on sp2 (e.g., vinyl, aryl, acyl (C=O)) or sp (ethynyl) carbons do not react in fashion described in this section((

 Nucleophiles&
Donate'a'pair'of'electrons:'to'an'electrophile'(lone'pair'or'pi'bond)' Neutral& Anionic&

Electrophiles&
Receive'a'pair'of'electrons:'from'a'nucleophile' CaKonic&

Polar,&electrophilic&

 Eect&of&Leaving&Groups&on&Electrophilicity&

CWL&bond&must&be&relaKvely&weak& CWL&bond&must&be&polarizable'(the&ease&with&which&the&electron&distribuKon&in&the& bond&is&distorted&in&an&electric&eld)& L&needs&to&be&able&to&accommodate&a&pair&of&electrons& &Good&leaving&groups&are&weak&bases&&

TWO&CLASSES&OF&REACTION&
SubsKtuKon&reacKons&can&be&performed&under&dierent&condiKons&which&give&rise& to&dramaKcally&dierent&outcomes.&&Nucleophilic(subs9tu9on(reac9ons(can(be( classied(as(one(of(two(types,&based&on&these&experimental&observaKons.&&& In&order&to&develop&predicKve&tools,&we&need&to'understand'reasons'why'these& observaKons&are&important.&&That&is,&we&need&to&develop&proposals&for&two( dierent(mechanisms(which&are&consistent&with&the&two&sets&of&data&and&which'we' can'use'to'predict'the'outcome'of'other'reac<ons.'

SUBSTITUTION(AT(1(SUBSTRATES:( BIMOLECULAR(NUCLEOPHILIC(( SUBSTITUTION((SN2)(

Examples&

S:6.6-6.8

A(Mechanism(for(the(SN2(Reac9on(

A&transi<on'state&is&the&high&energy&state&of&the&reacKon.&&It&is&an&unstable&enKty&with&a& very&brief&existence&(10W12&s).&&In&the&transiKon&state&of&this&reacKon&bonds&are&parKally& formed&and&broken.&&Both&chloromethane&and&hydroxide&ion&are&involved&in&the& transiKon&state&and&this&explains&why&the&reacKon&is&second&order.&

Kine9cs(of(an(SN2(Reac9on(
The&iniKal&rate&of&the&following&reacKon&is&measured.&

The&rate&is&directly&proporKonal&to&the&iniKal&concentraKons&of&both&methyl&chloride&and& hydroxide&ion.&&The&rate&equaKon&reects&this&dependence.&&Methyl&chloride&and& hydroxide&ion&are&involved&in&the&rateWcontrolling&step&of&the&reacKon&or&in&a&step&prior&to& the&rateWcontrolling&step.& SN2$reac)on:$subsKtuKon,&nucleophilic,&2nd&order&(bimolecular).&

Transi9on(State(Theory:(FreeSEnergy(Diagrams(
Exergonic'reac<on:'negaKve&Go&(products&favored).& Endergonic'reac<on:'posiKve&Go&(products&not&favored).& The&reacKon&of&chloromethane&with&hydroxide&is&highly&exergonic. & &&

The&equilibrium&constant&is&very&large.&

An&energy&barrier&is&evident&because&a&bond&is&being&broken&in&going&to&the&transiKon& state&(which&is&the&top&of&the&energy&barrier).&&The&dierence&in&energy&between& starKng&material&and&the&transiKon&state&is&the&free'energy'of'ac<va<on'(G').''The& dierence&in&energy&between&starKng&molecules&and&products&is&the&free'energy'change' of'the'reac<on,''Go.'

A(Free(Energy(Diagram(of(a(Typical(SN2(Reac9on(

In&a&highly&endergonic&reacKon&of&the&same&type&the&energy&barrier&will&be&even& higher&(G&is&very&large).&

There&is&a&direct&relaKonship&between&G&and&the&temperature&of&a&reacKon.&&The& higher&the&temperature,&the&faster&the&rate.& Where&e&=&2.718&and&ko&is&the&absolute&rate&constant&[the&rate&at&which&all&transiKon& states&proceed&to&products&(6.2&x&1012&secW1)].&&Near&room&temperature,&a&10oC&increase& in&temperature&causes&a&doubling&of&rate.&&Higher&temperatures&cause&more&molecules& to&collide&with&enough&energy&to&reach&the&transiKon&state&and&react.&

The&energy&diagram&for&the&reacKon&of&chloromethane&with&hydroxide:&

A&reacKon&with&G&above&84&kJ&molW1&will&require&heaKng&to&proceed&at&a&reasonable& rate.&&This&reacKon&has&G&=&103&kJ&molW1&so&it&will&require&heaKng.&

In'Class'Problem:' What&is&the&eect&of&doubling&the&concentraKon&of&potassium&acetate&in&the& following&SN2&reacKon?&

The(Stereochemistry(of(SN2(Reac9ons(
Backside&ahack&of&nucleophile&results&in&an&inversion'of'congura<on.&&ConguraKon& describes&a&parKcular&arrangement&of&atoms&around&the&reacKng&carbon&center.&

In&cyclic&systems&a&cis&compound&can&react&and&become&trans&product.&

SN2'reac<ons'always'occur'with'inversion'of'congura<on.'

Nucleophilicity

Basicity and nucleophilicity are not the same, but they are related phenomena A negatively charged nucleophile is more reactive than its conjugate acid. CN > HCN OH > H O RO > ROH 2 In a group of nucleophiles in which the nucleophilic atom is the same, nucleophilicity parallels trends in basicity. RO > HO >> RCO2 >> ROH > H2O Steric bulk hinders nucleophilicity

Across a row in the periodic table, nucleophilicity parallels trends in basicity. CH3 > H2N > HO > F NH3 > H2O

 Choice&of&Solvents&for&Nucleophilic&SubsKtuKons&

The&solvent&dissolves&the&organic&substrate&(alkyl&halides&are&not&very&polar),&and& the&source&of&the&nucleophile&(oien&a&salt)&
H 2O CH3CO2H MeOH EtOH polar protic

(CH3)2SO DMSO

dimethyl sulfoxide

CH3CN AN actonitrile polar aprotic (CH3)2NCHO DMF CH3COCH3 CH2Cl2 - THF Et2O ether non-polar CH3(CH2)4CH3 benzene N,N-dimethylformamide acetone methylene chloride tetrahydrofuran diethyl ether

Pro<c'solvents'solvate&the&anions&(nucleophiles)&by& HWbonding&and&caKons&(counterions).&&Small& electronegaKve&anions&are&parKcularly&well& solvated,&lowering&their&nucleophilicity.&& Trends'in'nucleophilicity'in'polar'pro<c'solvents' increases'going'down'a'column'of'the'periodic' table' & F&j& & Cl&j& & Br&j& & I&j& Polar'apro<c'solvents&cannot&hydrogen&bond&to& anions&(but&do&solvate&caKons).&& Trends'in'nucleophilicity'in'polar'apro<c'solvents' parallels'trends'in'basicity.'' & F&j& & Cl&j& & Br&j& & I&j& Polar&aproKc&solvents&are&oien&a&good&choice&for& SN2&reacKons&(Ij&is&sKll&suciently&nucleophilic)&

Nucleophilicity of anions

nucleophilicity
base strength

He

nucleophilicity in APROTIC solvents (

nucleophilicity in protic solvents (

Li

Be

C CH3

N NH2 P

Ne

OH
S

F
Cl Ar base strength

Na

Mg

Al

Si

SH
Se

Cl
Br

Ca

Ga

Ge

As

Kr

SeH

Br
I

Neutral nucleophiles H2S, R3P are highly polarizable and can donate more electron density than smaller neutral nucleophiles (e.g., H2O; R3N), independent of solvent.

Relative Nucleophilicity (in MeOH)&&

Relative Nucleophilicity Excellent Nucleophiles CN HS I Good Nucleophiles
OH

Cyanide Thiolate Iodide Hydroxide Bromide Azide Ammonia Nitrite Chloride Acetate Fluoride Methanol Water

126,000 126,000 80,000 16,000 10,000 10,000 8000 5000 1000 630 80 1 1

Br N 3 NH3 NO2 Fair Nucleophiles Cl CH3COO F CH3OH H 2O

Nucleophilic relative strength is measured by relative rate in an SN2 reaction (but depends on substrate, solvent type, etc.)

Remember&W&anions&can&act&as&nucleophiles&or'bases;&you&cannot&use&a&strongly&basic& nucleophile&in&a&proKc&solvent!&

The&solvent&needs&to&be&less&acidic&than&NuWH&

&&&&Leaving&Group&Ability&
& & & & ''&&&Rate:&IW&>&WBr&>&WCl&>>&WF& CWL&bond&must&be&broken&&weaker&bonds&are&more&polarizable,&easier&to&break& & Bond&strengths&(kcal/mole):&& & & & & &CWF&&&&&&&&116& &CWCl&&&&&&&&79& &CWBr&&&&&&&66& &CWI&&&&&&&&&&52&

Overall:&&A&good&substrate&for&bimolecular&nucleophilic&subsKtuKon&should&have:&

1. Weak(CSL(bond( 2. Polarizable(CSL(bond(( 3. Leaving(group(that(can(accommodate(a(pair(of(electrons(

Leaving group Good Leaving Groups I Br Cl RSO3 H 2O Very Poor Leaving Groups Iodide Bromide Chloride Sulfonate Water

pKa of conjugate acid -10 -9 -7 -6.5 -1.7

F HS
CN

Fluoride Thiolate Cyanide Hydroxide Alkoxide Hydride

2 3

3.2 7 9.2 15.7 16-18 35 38 48

HO RO H
NH CH

Amino Methyl

 How&can&iodide&be&a&good&nucleophile&and&a&good& leaving&group?&

Energy

Reaction Coordinate

Ea&for&RL&&RI&&is&lower&than&for&RL&&RCl&&&&Ij&is&a&beher&nucleophile& Ea&for&RI&&RL&&is&lower&than&for&RCl&&RL&&&I&j&is&a&beher&leaving&group&

Polarizability of I as a nucleophile

Polarizability of C-I bond: I as a leaving group

Nu

Nu

Alkyl Substrates

Rate: methyl > 1 > 2 ( 3 unreactive)

Me

Et

iPr

tBu

Adjacent alkyl groups also slow the reaction

SUMMARY: FACTORS EFFECTING SN2 REACTIONS

S:6.15;

One-step (concerted) mechanism Substrate: Methyl>1>2>>3 - Steric bulk hinders attack of Nu Rate = k [substrate] [nucleophile] Chirality - Inversion Often performed in polar aprotic solvents, e.g., DMF (Me2NCHO), DMSO (Me2SO) to dissolve substrate and ionic reagent, and increase reaction rate

 Prac9cal(Applica9ons(of(SN2(Reac9ons:(Func9onal(Group( Transforma9ons(at(1o(and(2o(Carbons(
source of nucleophile

Synthesis(of(Alkynes(and(Alkanes:(Alkyla9on(of( Acetylide(Anions(

 Problem:&How&would&you&prepare&2Wphenylethanethiol&from&1WiodoW2W phenylethane?&

Problem:'How&would&you&make&the&following&compound&from&1W bromopropane&and&any&other&starKng&materials?&

Problem:'Which'of'the'following'would'undergo'the'fastest'reac<on'with'1N bromopropane?' (a)&&&Ph3N&&&&or&&&&&&Ph3P&

(b)&&1.0&M&CH3ONa&&&&&&or&&&&&&2.0&M&CH3ONa&

~ MAKE FLASHCARDS ~

'''''''''''''''''''''''''''''''''''''front'''''''''''''''''''''back'
Substrate&+&Reagent& (and&condiKons)& Product(s)&

Substrate&& and&Product&

Reagents&(and& condiKons)&

Reagent&(and& condiKons)&and& Product&

Substrate&

S:6.9-6.13

SUBSTITUTION(AT(3(SUBSTRATES:( UNIMOLECULAR(NUCLEOPHILIC(SUBSTITUTION((SN1)(
tertWButyl&chloride&undergoes&subsKtuKon&with&hydroxide.&&The&rate&is&independent&of& hydroxide&concentraKon&and&depends&only&on&concentraKon&of&tertWbutyl&chloride.&&The& rate&equaKon&is&rst&order&with&respect&to&tertWbutyl&chloride&and&rst&order&overall.&

SN1'reac<on:'SubsKtuKon,&nucleophilic,&1st&order&(unimolecular).& The&rate&depends&only&on&the&concentraKon&of&the&alkyl&halide.&&Only&the&alkyl&halide&(and& not&the&nucleophile)&is&involved&in&the&transiKon&state&of&the&step&that&controls&the&rate.&

Mul9step(Reac9ons(and(the(RateSDetermining(Step(
In&mulKstep&reacKons,&the&rate&of&the&overall&reacKon&will&be&essenKally&the&same&as&the& rate&of&the&slowest&step.&&This&is&called&the&rateWlimiKng&step&or&the&rateW&determining& step.&&In&the&case&below&k1<<k2&or&k3&and&the&rst&step&is&rate&determining.&

A(Mechanism( for(the(SN1( Reac9on( Step&1&is&rate& determining& (slow)&because& it&requires&the& formaKon&of& unstable&ionic& products.&&In& step&1&water& molecules&help& stabilize&the& ionic&products.&

Carboca9ons(
A&carbocaKon&has&only&6&electrons,&is&sp2&hybridized&and&has&an&empty&p&orbital& normal&to&the&caKonic&center&and&the&three&atoms&ahached&to&this&center.&

The&more&alkyl&groups&ahached&to&the&carbocaKonic&center&the&more&stable&the& carbocaKon.&&The&more&stable&a&carbocaKon&is,&the&easier&it&is&to&form.&

Hyperconjuga<on&stabilizes&the&carbocaKon&by&donaKon&of&electrons&from&an&adjacent& &carbonWhydrogen&or&carbonWcarbon&&bond&into&the&empty&p&orbital.&&&More& subsKtuKon&provides&more&opportunity&for&hyperconjugaKon.&

Kinetics"

" "

"[t-Bu-Hal] 0.01 M " 0.02 M 0.01 M " 0.02 M "

[H-Nu:] 0.01 M 0.01 M 0.02 M 0.02 M

relative rate" "1" "2" "1" "2"

Result: Rate = k[R-L] independent of concentration of Nu"

Solvolysis(
A&molecule&of&the&solvent&is&the&nucleophile&in&a&subsKtuKon&reacKon.&&If&the&solvent&is& water&the&reacKon&is&a&hydrolysis.&&If&the&solvent&is&methanol&or&formic&acid,&the&reacKon& is&methanolysis&or&formolysis,&repecKvely.&

These&reacKons&arise&because&solvents&which&are&polar&enough&to&facilitate&dissociaKon& of&the&substrate&are&also&nucleophilic.&

The(Stereochemistry(of(SN1(Reac9ons(
When&the&leaving&group&leaves&from&a&stereogenic&center&of&an&opKcally&acKve& compound&in&an&SN1&reacKon&racemizaKon&will&occur.&&The&reason&is&that&an&achiral& carbocaKon&intermediate&is&formed.& Racemiza<on:&transformaKon&of&an&opKcally&acKve&compound&to&a&racemic&mixture.&

The(Stereochemistry(of(SN1(Reac9ons(

In'Class'Problem:' Explain&the&following&observaKon.&&(S)W3WBromoW3Wmethylhexane&reacts&in&aqueous& acetone&to&give&racemic&3WmethylW3Whexanol.&

Factors(Aec9ng(the(Rate(of(SN1(and(SN2(Reac9ons( The(Eects(of(the(Structure(of(the(Substrate&
(1) Structure&of&the&substrate.& (2) ConcentraKon&and&reacKvity&of&the&nucleophile&(for&bimolecular&reacKons).& (3) Eect&of&solvent.& (4) Nature&of&the&leaving&group.&

Factors(Aec9ng(the(Rate(of(SN1(and(SN2(Reac9ons( The(Eects(of(the(Structure(of(the(Substrate(
SN2$Reac)ons:$ In&SN2&reacKons&alkyl&halides&show&the&following&general&order&of&reacKvity.&

Steric'hinderance:'the&spaKal&arrangement&of&the&atoms&or&groups&at&or&near&a&reacKng& site&hinders&or&retards&a&reacKon.&&In&terKary&and&neopentyl&halides,&the&reacKng&carbon& is&too&sterically&hindered&to&react&at&an&appreciable&rate&by&the&SN2&mechanism.&

SN1$reac)ons$ Organic&compounds&that&undergo&reacKon&by&an&SN1&path&at&a&reasonable&rate&are&those& that&are&capable&of&forming&relaKvely&stable&carbocaKons&such&as&terKary&halides,&allyl& halides&and&benzyl&halides.& The$Hammond5Leer$Postulate$ The&transiKon&state&for&an&exergonic&reacKon&looks&very&much&like&starKng&material.&&The& transiKon&state&for&an&endergonic&reacKon&looks&very&much&like&product.&&Generally&the& transiKon&state&looks&most&like&the&species&it&is&closest&to&in&energy&

In&the&rst&step&of&the&SN1&reacKon&the&transiKon&state&looks&very&much&like& carbocaKon&intermediate.&&The&carbocaKonWlike&transiKon&state&is&stabilized&by&all&the& factors&that&stabilize&carbocaKons.&&The&transiKon&state&leading&to&terKary& carbocaKons&is&much&more&stable&and&lower&in&energy&than&transiKon&states&leading& to&other&carbocaKons&such&as&secondary&carbocaKons.&

Vinylic(and(phenyl(halides&are&generally&unreacKve&in&SN1&and&SN2&reacKons.&

SN1(Reac9on:( Rate&does(not(depend(on(the(iden9ty(or(concentra9on(of(nucleophile( SN2(Reac9on:( Rate&is&directly(propor9onal(to(the(concentra9on(of(nucleophile.&&Stronger& nucleophiles&also&react&faster.&&A&negaKvely&charged&nucleophile&is&always&more& reacKve&than&its&neutral&conjugate&acid.&&When&comparing&nucleophiles&with&the&same& nucleophilic&atom,&nucleophiliciKes&parallel&basiciKes.&

The(Eects(of(the(Concentra9on(and(Strength(of( Nucleophile(

Methoxide&is&a&much&beher&nucleophile&than&methanol.&

Solvent(Eects(on(SN2(Reac9ons:( Polar(Pro9c(and(Apro9c(Solvents(
Polar(Pro9c(Solvents:(Polar&solvents&that&have(a(hydrogen(atom(ahached&to&strongly& electronegaKve&atoms.&&They&solvate&nucleophiles&and&make&them&less&reacKve.&

Larger&nucleophilic&atoms&are&less&solvated&and&therefore&more&reacKve&in&polar&proKc& solvents.&&Larger&nucleophiles&are&also&more&polarizable&and&can&donate&more&electron& density.& RelaKve&nucleophilicity&in&polar&solvents:&

Polar(Apro9c(Solvents:(Polar&aproKc&solvents&do(not(have(a(hydrogen&ahached&to&an& electronegaKve&atom.&

They&solvate&caKons&well&but&leave&anions&relaKvely&unsolvated.&

Polar&proKc&solvents&lead&to&generaKon&of&naked&and&very&reacKve&nucleophiles.&& Trends&for&nucleophilicity&are&oien&the&same&as&for&basicity.&&They&are&excellent&solvents& for&SN2&reacKons.&

Solvent(Eects(on(SN1(Reac9ons:( The(Ionizing(Ability(of(the(Solvent(
Polar&proKc&solvents&are&excellent&solvents&for&SN1&reacKons.&&Polar&proKc&solvents& stabilize&the&carbocaKonWlike&transiKon&state&leading&to&the&carbocaKon&thus&lowering& G.&&In&order&to&increase&the&solubility&of&alkyl&halides&mixed&solvent&systems&are&oien& used.&&WaterWethanol&and&waterWmethanol&mixtures&are&most&common&solvent& mixtures.&

The(Nature(of(the(Leaving(Group(
The&best(leaving(groups(are&weak(bases(which(are(rela9vely(stable.&&& The&leaving&group&can&be&an&anion&or&a&neutral&molecule.& Leaving&group&ability&of&halides:& This&trend&is&opposite&to&basicity:& Other&very&weak&bases&which&are&good&leaving&groups:&

The&poor&leaving&group&hydroxide&can&be&changed&into&the&good&leaving&group&water&by& protonaKon.&

SUMMARY: FACTORS EFFECTING SN1 AND SN2 REACTIONS

SN1 SN2

S:6.15;

Dissociation-Nucleohipic addition-Deprotonation

One-step (concerted) mechanism

Substrate: 3>2>>1or methyl - Stability of carbocation intermediate Rate = k [substrate] - independent of [nucleophile] - rate depends on solvent polarity Chirality - racemization Generally only useful for solvolyses (reactions with H2O, ROH, RCO2H)

Substrate: Methyl>1>2>>3 - Steric bulk hinders attack of Nu Rate = k [substrate] [nucleophile] Chirality - Inversion Often performed in polar aprotic solvents, e.g., DMF (Me2NCHO), DMSO (Me2SO) to dissolve substrate and ionic reagent, and increase reaction rate

Summary(SN1(vs.(SN2(
In&both&SN2&and&SN1&reacKons&alkyl&iodides&react&the&fastest&than&alkyl&bromides&which& react&faster&than&alkyl&chlorides&because&iodide&is&a&leaving&group&than&bromide&which&is& beher&than&chloride.&

In'Class'Problems:' For&each&of&the&following&pairs&of&reacKons,&predict&which&one&is&faster&and& explain&why.&

Alcohols(as(Acids(

S:11.6-11.9

Alcohols&have&acidiKes&similar&to&water.&&Sterically&hindered&alcohols&such&as&tertWbutyl& alcohol&are&less&acidic&(have&higher&pKa&values).&&Why?:&The&conjugate&base&is&not&well& solvated&and&so&is&not&as&stable.&

Alcohols&are&stronger&acids&than&terminal&alkynes&and&primary&or&secondary&amines.&

An&alkoxide&can&be&prepared&by&the&reacKon&of&an&alcohol&with&sodium&or&potassium& metal.&

Conversion(of(Alcohols(into(Alkyl(Halides(
Hydroxyl&groups&are&poor&leaving&groups,&and&as&such,&are&oien&converted&to&a&group& that&can&depart&as&a&weak&base;&hydroxyl&groups&are&converted&to&good&leaving&groups.& Three'general'methods&exist&for&conversion&of&alcohols&to&alkyl&halides,&depending&on& the&classicaKon&of&the&alcohol&and&the&halogen&desired.&&ReacKon&can&occur&with& hydrogen&halides,&phosphorus&tribromide,&or&thionyl&chloride.&

Alkyl(Halides(from(the(Reac9on(of(Alcohols( with(Hydrogen(Halides(
The&order&of&reacKvity&is&as&follows:&HI&&>&&HBr&&>&&HCl&>&HF.&&Type&of&alcohol&3o&>&2o&>&1o&<& methyl.& Mechanism'of'the'Reac<on'of'Alcohols'with'HX:&&SN1&mechanism&for&3o,&2o,&allylic&and& benzylic&alcohols.&&These&reacKons&are&prone&to&carbocaKon&rearrangements.& In&Step'1&the&hydroxyl&is&converted&to&a&good&leaving&group&by&protonaKon&to&form&the& corresponding&oxonium&ion.&

In&Step'2&the&leaving&group&departs&as&a&water&molecule,&leaving&behind&a&carbocaKon&

In&Step'3&the&halide,&a&relaKvely&good&nucleophile,&reacts&with&the&carbocaKon.&

Primary&and&methyl&alcohols&undergo&subsKtuKon&by&an&SN2&mechanism.&

Primary&and&secondary&chlorides&can&only&be&made&with&the&assistance&of&a&Lewis&acid& such&as&zinc&chloride.&

In'Class'Problem:' Outline&a&reasonable&mechanism&for&the&following&reacKon:&

Alkyl(Halides(from(the(Reac9on(of(Alcohols(with( PBr3(and(SOCl2(
These&reagents&only&react&with&1o&and&2o&alcohols&by&means&of&an&SN2&mechanism.&&In& each&case&the&reagent&converts&the&hydroxyl&to&an&excellent&leaving&group.&&No& rearrangements&are&seen.& Reac<on'of'phosphorous'tribromide'to'give'alkyl'bromides:'

Reac<on'of'thionyl'chloride'to'give'alkyl'chlorides:'

Mechanism:'

Oien&an&amine&is&added&to&react&with&HCl&formed&in&the&reacKon.&

The&hydroxyl&group&of&an&alcohol&can&be&converted&to&a&good&leaving&group&by&conversion& to&a&sulfonate&ester.&

Tosylates,(Mesylates,(and(Triates:( Leaving(Group(Deriva9ves(of(Alcohols&

Sulfonyl&chlorides&are&used&to&convert&alcohols&to&sulfonate&esters.&&Base&is&added&to&react& with&the&HCl&generated.&

A&sulfonate&ion&(a&weak&base)&is&an&excellent&leaving&group.&

If&the&alcohol&hydroxyl&group&is&at&a&stereogenic&center&then&the&overall&reacKon&with&the& nucleophile&proceeds&with&inversion&of&conguraKon.&&The&reacKon&to&form&a&sulfonate& ester&proceeds&with&retenKon&of&conguraKon.&

Triate&anion&is&such&a&good&leaving&group&that&even&vinyl&triates&can&undergo&SN1& reacKon.&

In'Class'Problem:' Draw&the&conguraKons&of&the&products&when&(R)W1Wphenylethanol&is&rst&reacted& with&pWtoluenesulfonyl&chloride&followed&by&reacKon&with&potassium&acetate.&

Synthesis(of(Ethers(

S:11.11-12

(1)&Ethers'by'Intermolecular'Dehydra<on'of'Alcohol:''Primary&alcohols&can&dehydrate&to& ethers.&&This&reacKon&occurs&at&lower&temperature&than&the&compeKng&dehydraKon&to& an&&alkene.&&This&method&generally&does&not&work&with&secondary&or&terKary&alcohols& because&eliminaKon&dominates.&

The&reacKon&proceeds&by&an&SN2&mechanism:&

(2)&Williamson'Ether'Synthesis:&This&is&a&good&route&for&synthesis&of&unsymmetrical&ethers.&

The&alkyl&halide&(or&alkyl&sulfonate)&should&be&primary&to&avoid&an&E2&reacKon.&& SubsKtuKon&is&favored&over&eliminaKon&at&lower&temperatures.&

(3)&Silyl'Ether'Protec<ng'Groups:'Silyl&ethers&are&widely&used&protecKng&groups&for& alcohols.&&The&tertWbutyl&dimethysilyl&(TBDMS)&ether&is&a&common&protecKng&group.&&The& protecKng&group&is&introduced&by&reacKon&of&the&alcohol&with&the&appropriate& chlorosilane&&in&the&presence&of&an&aromaKc&amine&base&such&as&imidazole&or&pyridine.&&&

The&silyl&ether&protecKng&group&is&easily&removed&by&treatment&with&uoride&ion&(e.g.& from&tetrabutyl&ammonium&uoride).&

Reac9ons(of(Ethers(
Acyclic&ethers&are&generally&unreacKve,&except&for&cleavage&by&very&strong&acids&to& form&the&corresponding&alkyl&halides.&&Dialkyl&ethers&undergo&sequenKal&SN2&reacKons& with&HBr&to&form&2&equivalents&of&the&alkyl&bromide.&

Intramolecular(SN2(Reac9ons(
Epoxides&are&threeWmembered&ring&cyclic&ethers.&&These&groups&are&also&called& oxiranes.&&They&can&be&prepared&by&an&intramolecular&SN2&reacKon.&

Intramolecular&subsKtuKons&oien&results&in&the&formaKon&of&rings.&

Reac9on(of(Epoxides(
Epoxides&are&considerably&more&reacKve&than&regular&ethers.&&The&threeWmembered& ring&is&highly&strained&and&therefore&very&reacKve.&&AcidNcatalyzed'opening'of'an' epoxide&occurs&by&iniKal&protonaKon&of&the&epoxide&oxygen,&making&the&epoxide&even& more&reacKve.&&AcidWcatalyzed&hydrolysis&of&an&epoxide&leads&to&a&1,2Wdiol.&

In&unsymmetrical&epoxides,&the&acid&catalyzed&ring&opening&reacKon&usually&proceeds& through&the&most&stable&incipient&carbocaKon;&the&nucleophile&ahacks&primarily&at&the& most&subsKtuted&carbon&of&the&epoxide.&&&

BaseNcatalyzed'reac<on&with&strong&nucleophiles&(e.g.&an&alkoxide&or&hydroxide)&occurs& by&an&SN2&mechanism.&&The&nucleophile&ahacks&at&the&least&sterically&hindered&carbon&of& the&epoxide.&

Problem: How would you prepare 2-phenylethanethiol from 2-phenyl-1ethanol?

Problem: How would you make the following product from 1-propanol and any other starting materials?

Homolysis(and(Radicals(Revisited(

S:4.16, 10.2-10.6

HomolyKc&bond&cleavage&leads&to&the&formaKon&of&radicals&(also&called&free&radicals).&& Radicals&are&highly&reacKve,&shortWlived&species.&&SingleWbarbed&arrows&are&used&to&show& the&movement&of&single&electrons.&

Produc<on'of'Radicals:&&Homolysis&of&relaKvely&weak&bonds&such&as&OWO&or&XWX&bonds& can&occur&with&addiKon&of&energy&in&the&form&of&heat&or&light.&

Reac<ons'of'Radicals:&Radicals&tend&to&react&in&ways&that&lead&to&pairing&of&their& unpaired&electron.&&Hydrogen&abstracKon&is&one&way&a&halogen&radical&can&react&to&pair& its&unshared.&&

Homoly<c'Bond'Dissocia<on'Energies:&Atoms&have&higher&energy&(are&less&stable)&than& the&molecules&they&can&form.&&The&formaKon&of&covalent&bonds&is&exothermic.&&Breaking& covalent&bonds&requires&energy&(i.e.&is&endothermic).&

The&homolyKc&bond&dissociaKon&energy&is&abbreviated&DHo.&

Homoly<c'Bond'Dissocia<on'Energies'and'Heats'of'Reac<on:&HomolyKc&bond& dissociaKon&energies&can&be&used&to&calculate&(esKmate)&the&enthalpy&change&(Ho)&for&a& reacKon.&&DHo&is&posiKve&for&bond&breaking&and&negaKve&for&bond&forming.& Example:&& This&reacKon&below&is&highly&exothermic&since&Ho&is&a&large&and&negaKve.&&Ho&is&not& dependant&on&the&mechanism;&only&the&iniKal&and&nal&states&of&the&molecules&are& considered&in&determining&Ho.&

Homoly<c'Bond'Dissocia<on'Energies'and'the'Rela<ve'Stabili<es'of'Radicals:'The& formaKon&of&dierent&radicals&from&the&same&starKng&compound&oers&a&way&to&esKmate& relaKve&radical&stabiliKes.& Examples:' The&propyl&radical&is&less&stable&than&the&isopropyl&radical.&

Likewise&the&tertWbutyl&radical&is&more&stable&than&the&isobutyl&radical.&

The&energy&diagrams&for&these&reacKons&are&shown&below.&

The&rela<ve'stabili<es'of'radicals&follows&the&same&trend&as&for&carbocaKons.&&The&most& subsKtuted&radical&is&most&stable.&&Radicals&are&electron&decient,&as&are&carbocaKons,& and&are&therefore&also&stabilized&by&hyperconjugaKon.&

In'Class'Problem:' List&the&following&organic&radicals&in&the&order&of&increasing&stability.&

Radical(Subs9tu9ons:( The(Reac9ons(of(Alkanes(with(Halogens(
Alkanes&undergo&subsKtuKon&reacKons&with&halogens&such&as&uorine,&bromine&and& chlorine&in&the&presence&of&heat&or&light.&

Mul<ple'Subs<tu<on'Reac<ons'versus'Selec<vity:''Radical&halogenaKon&can&yield&a& mixture&of&halogenated&compounds&because&all&hydrogen&atoms&in&an&alkane&are& capable&of&subsKtuKon.&&In&the&reacKon&above&all&degrees&of&methane&halogenaKon&will& be&seen.&&MonosubsKtuKon&can&be&achieved&by&using&a&large&excess&of&the&alkane.&&A& large&excess&of&methane&will&lead&to&predominantly&monohalogenated&product&and& excess&unreacted&methane.&

ChlorinaKon&of&higher&alkanes&leads&to&mixtures&of&monochlorinated&product&(and&more& subsKtuted&products).&&Chlorine&is&relaKvely&unselec<ve&and&does&not&greatly&disKnguish& between&type&of&hydrogen.&&

Molecular&symmetry&is&important&in&determining&the&number&of&possible&subsKtuKon& products.&

Bromine&is&less&reacKve&but&more&selecKve&than&chlorine&(Sec.&10.6A).&

Selec<vity'of'Chlorine:'MonochlorinaKon&of&alkanes&proceeds&to&give&some&selecKvity.&& TeriKary&hydrogens&are&somewhat&more&reacKve&than&secondary&hydrogens&which&are& more&reacKve&than&primary&hydrogens.&&Eact&for&abstracKon&of&a&terKary&hydrogen&is&lower& because&of&increased&stability&of&the&intermediate&terKary&radical.&&The&dierences&in&rate& of&abstracKon&are&not&large&and&chlorinaKon&occurs&so&rapidly&it&cannot&disKnguish&well& between&classes&of&hydrogen&and&so&is&not&very&selecKve.&

Selec<vity'of'Bromine:&Bromine&is&much&less&reacKve&but&more&selecKve&than&chlorine&in& radical&halogenaKon.&&Fluorine&shows&almost&no&discriminaKon&in&replacement&of& hydrogens&because&it&is&so&reacKve.&

Chlorina9on(of(Methane:(Mechanism(of(Reac9on(
The&reacKon&mechanism&has&three&disKnct&aspects:&(1)&chain&iniKaKon,&(2)&chain& propagaKon&and&(3)&chain&terminaKon.& Chain'ini<a<on:' Chlorine&radicals&form&when&the&reacKon&mixture&is&subjected&to&heat&or&light.&&Chlorine& radicals&are&used&in&the&chain&propagaKon&steps&below.&

Chain'propaga<on: && A&chlorine&radical&reacts&with&a&molecule&of&methane&to&generate&a&methyl&radical.&&A& methyl&radical&reacts&with&a&molecule&of&chlorine&to&yield&chloromethane&and&regenerate& chlorine&radical.&&A&chlorine&radical&reacts&with&another&methane&molecule,&conKnuing&the& chain&reacKon.&&A&single&chlorine&radical&can&lead&to&thousands&of&chain&propagaKon&cycles.&

Chain'reac<on:'a&stepwise&mechanism&in&which&each&step&generates&the&reacKve& intermediate&that&causes&the&next&cycle&of&the&reacKon&to&occur.& Chain'termina<on:' Occasionally&the&reacKve&radical&intermediates&are&quenched&by&reacKon&pathways&that& do&not&generate&new&radicals.&&The&reacKon&of&chlorine&with&methane&requires&constant& irradiaKon&to&replace&radicals&quenched&in&chainWterminaKng&steps.&

The&enKre&mechanism&is&shown&below.&

Chlorina<on'of'Methane:'Energy'Changes

&&

The&chain&propagaKon&steps&have&overall&Ho=&W101&kJ&molW1&and&are&highly&exothermic.&

Reac9on(of(Methane(with(Other(Halogens(
The&order&of&reacKvity&of&methane&subsKtuKon&with&halogens&is:&uorine&&>&chlorine&>& bromine&>&iodine.&&The&order&of&reacKvity&is&based&on&the&values&of&Eact&for&the&rst&step&of& chain&propagaKon&and&Ho&for&the&enKre&chain&propagaKon.&&FluorinaKon&has&a&very&low& value&for&Eact&in&the&rst&step&and&Ho&is&extremely&exothermic&therefore&uorinaKon& reacKons&are&explosive.&&ChlorinaKon&and&brominaKon&have&increasingly&higher&values&of& Eact&and&lower&overall&Ho&values&which&makes&these&halogenaKon&reacKons&less&vigorous.&& IodininaKon&has&a&prohibiKvely&high&value&for&Eact&of&the&rst&step&and&the&reacKon&does&not& occur.&&The&energy&values&of&the&iniKaKon&step&are&unimportant&since&they&occur&so&rarely.& On&the&basis&of&Ho&&values&for&the&iniKaKon&step&iodinaKon&should&be&most&rapid.&

Reac9ons(that(Generate(Tetrahedral( Stereogenic(Carbons(
A&reacKon&of&achiral&starKng&materials&which&produces&a&product&with&a&stereogenic& carbon&will&produce&a&racemic&mixture.&

Genera9on(of(a(Second(Stereogenic(Carbon(in(a( Radical(Halogena9on(
When&a&molecule&with&one&or&more&stereogenic&carbons&undergoes&halogenaKon&to& create&another&stereogenic&carbon,&the&two&diastereomeric&products&are&not&produced& in&equal&amounts.&&The&intermediate&radical&is&chiral&and&reacKons&on&the&two&faces&of& the&radical&are&not&equally&probable.&

SUBSTITUTIONS(IN(SYNTHESIS(
You should prepare a chart of all of the types of reactions that have been covered so far .well add more later.

S:4.18-19

ONE-STEP SYNTHESES
It is important to recognize transformations which can be performed in a single step. Use the thought process: - What can the product can be made from? PRODUCT STARTING MATERIAL - The synthesis itself is STARTING MATERIAL PRODUCT

 SN&reacKons&allow&for&interconversions&of&funcKonal&groups,&which&will&be&useful&in& further&transformaKons.&How&would&you&prepare&the&following&nitrile?&

&

&

& &

 SN2&reacKons&are&also&useful&in&preparing&larger&molecules&from&smaller&molecules& by&alkylaKon&of&acetylide&anions.&The&resulKng&alkyne&can&be&transformed&into& other&compounds.&How&would&you&prepare&the&following&alkyne&from&starKng& materials&with&7&or&fewer&carbon&atoms?&

& & & & &

An important limitation on acid catalyzed SN reactions tert-Butanol must be protonated to make the hydroxyl group a better leaving group. Ammonia is nucleophilic So why doesnt this reaction work?

Why cant you do this sequentially? i.e.,

Acid promoted SN2 reactions are limited to cases where the nucleophile is very weakly basic (i.e., reaction with H-Hal). For other nucleophiles, convert the alcohol to the tosylate or mesylate first.

The role of nucleophilicity, leaving group ability, and substrate on SN processes. Which of the following proceed efficiently?

What about secondary alkyl halides? 1 R-L: 3 R-L: 2 R-L: might display features of both SN1 and SN2 reactions (!) Under conditions strongly favoring SN1 reactions SN1 (polar solvent, poor nucleophile) Under conditions strongly favoring SN2 reactions SN2. (good nucleophile) ..but strongly basic nucleophiles promote elimination! (see Topic 7) What about vinyl halides and aryl halides?

TOPIC 6 ON EXAM 3
Types of Questions

- Recognize factors which influence the mechanism of nucleophilic and radical substitutions - Predict outcomes of substitution reactions - Design short syntheses - The problems in the book are good examples of the types of problems on the exam.
Preparing for Exam 3

- Work as many problems as possible. - Work in groups. - Do the Learning Group Problem at the end of the chapter. - Work through the practice exams

REVIEW PROBLEMS
Problem: Why does the following reaction not take place? CH3CH2CH3 + HO CH3CH2CH2OH + H

Problem: Explain why reaction of 1-bromopropane with potassium cyanide gives a mixture of CH3CH2CH2CN (major product) and CH3CH2CH2NC (minor)? Draw Lewis structures of the products and nucleophiles.

Problem: How can you prepare the following two compounds from the appropriate alkyl bromide? (a) Methyl phenyl ether, Me-O-Ph

(b) (S)-2-Pentanol, CH3CH(OH)CH2CH2CH3

 Problem:'How&could&you&perform&the&following&synthesis?&[An'introduc<on' to'designing'mul<Nstep'syntheses]'
'''' '''''''''''''''''''''''''''''''''''''''''''''''from'

Problem: Predict the structure of the product of the following reaction

In'Class'Problems:' Designate&the&nucleophile,&the&electrophile,&and&the&leaving&group&for&each&of& the&following&reacKons.&

In'Class'Problem:' (1) Draw&the&stereochemical&structures&for&the&reactant&and&product&for&the& reacKon&of&(S)W2Wchloropentane&with&chlorine.& (2) Indicate&the&stereochemical&conguraKon&at&each&of&the&chiral&carbons&in&the& products.& (3) Are&the&products&opKcally&acKve?& (4) Can&the&products&be&separated&by&convenKonal&means?&