Hydrolysisis Water, Is Applied.The Term Staphylococcus Aureus Bacteria (Opaque and Grey), an Organism Hydrolysis Is Applied

Organic Chemistry I

Mohammad Jafarzadeh Faculty of Chemistry, Razi University

Organic Chemistry, Structure and Function (7th edition) By P. Vollhardt and N. Schore, Elsevier, 2014 1 CHAPTER 7 Further Reactions of Haloalkanes Unimolecular Substitution and Pathways of Elimination

N O N O :Base

e have learned that the SN2 displacement process is an important reaction pathway for Whaloalkanes. But is it the only mechanism for displacement available? Or are there other, fundamen- tally different types of transformations that haloalkanes undergo? In this chapter, we shall see that haloalkanes can indeed follow reaction pathways other than SN2 displacement, especially if the haloalkanes are tertiary or secondary. In fact, bimolecular substitution is only one of four possible modes of reaction. The other three modes are unimolecular substitution and two types of elimination processes. The elimination processes give rise to double bonds through loss of HX and serve as our introduction into the prepara- 7. Further Reactionstion of multiply bonded organicof compounds.Haloalkanes

Medicinal chemists use many 7.1 SOLVOLYSIS OF TERTIARY7-1 SOLVOLYSISAND SECONDARY OF TERTIARYHALOALKANES AND SECONDARY HALOALKANES reactions to explore structure- activity relationships in physiologically active compounds. The rate of the SN2 Wereaction have learneddiminishes that the ratedrastically of the SN2 whenreactionthe diminishesreacting drasticallycenter whenchanges the reactingfrom Above, the bromocyclohexyl primary to secondarycenterto tertiary changes. from primary to secondary to tertiary. These observations, however, pertain substituent to a b-lactam is converted to a cyclohexenyl only to bimolecular substitution. Secondary and tertiary halides do undergo substitution, group by elimination of HBr. Secondary and tertiarybut byhalides another domechanism.undergo In fact,substitution, these substratesbut transformby another readily,mechanism even in the presence. In fact, b-Lactams are four-membered of weak nucleophiles, to give substitution products. ring amides featured in the these substrates transform readily, even in the presence of weak nucleophiles, to give structure of many antibiotics, such For example, when 2-bromo-2-methylpropane (tert-butyl bromide) is mixed with water, it as penicillin and cephalosporin, substitution productsis. rapidly converted into 2-methyl-2-propanol (tert-butyl alcohol) and hydrogen bromide. Water and their modi! cation is essential is the nucleophile here, even though it is poor in this capacity. Such a transformation, in which in combating drug resistance. Such a transformation, in which a substrate undergoes substitution by solvent molecules, is The photo shows Petri dish a substrate undergoes substitution by solvent molecules, is called solvolysis, such as methano- cultures of two strains of called solvolysis (e.lysis,g. methanolysis ethanolysis, and ,soethanolysis on. When the, solventetc.). isWhen water, thethe termsolvent hydrolysisis water, is applied.the term Staphylococcus aureus bacteria (opaque and grey), an organism hydrolysis is applied. An Example of Solvolysis: Hydrolysis that causes boils, abscesses, and urinary tract infections. At Poor nucleophile left, one bacterial strain shows yet fast reaction! CH3 CH3 sensitivity to penicillin (white A Relatively fast A pellet) as indicated by the clear

CH3CBršš ϩ HOšOH CH3CšOH ϩ HBršš zone of inhibited growth around A š š Aš š it. At right, a second strain of CH3 CH3 bacteria shows resistance to the drug and its growth is not 2-Bromo-2-methylpropane 2-Methyl-2-propanol inhibited. (tert-Butyl bromide) (tert-Butyl alcohol) 2 248 CHAPTER 7 Further Reactions of Haloalkanes 248 CHAPTER 7 Further Reactions of Haloalkanes

2-Bromopropane is hydrolyzed similarly, albeit much more slowly, whereas 1-bromopropane, bromoethane,2-Bromopropane and bromomethane is hydrolyzed similarly,are unchanged albeit muchunder morethese slowly,conditions. whereas 1-bromopropane, 2-Bromopropane is hydrolyzedbromoethane,similarly, and bromomethanealbeit much are unchangedmore slowly, under thesewhereas conditions.1-bromopropane, bromoethane,ReactionR and bromomethane are unchanged under these conditions. ReactionR Hydrolysis of a Secondary Haloalkane Hydrolysis of a Secondary Haloalkane CH3 CH3 A CH3 Relatively slow A CH3

CH3CBršAš ϩ HOšOH Relatively slow CH3COHšA ϩ HBršš Reminder CHA3šCBršš ϩ HOš šOH CHA3šCOHš ϩ šHBršš Reminder Nucleophile: red H A š š H Aš š Electrophile:Nucleophile: blue red 2-BromopropaneH 2-PropanolH LeavingElectrophile: group: greenblue (Isopropyl2-Bromopropane bromide) (Isopropyl2-Propanol alcohol) Leaving group: green (Isopropyl bromide) (Isopropyl alcohol) Methyl and Primary Methyl and Primary Solvolysis also takes place in alcohol solvents. Haloalkanes:Solvolysis also takes placeSolvolysisin alcohol also takessolvents place .in alcohol solvents. UnreactiveHaloalkanes: in Solvolysis Unreactive in Solvolysis CH Br Solvolysis of 2-Chloro-2-methylpropane in Methanol 3 Solvolysis of 2-Chloro-2-methylpropane in Methanol CH3CHCH23BrBr Solvolysis—the CH CH Br solventSolvolysis—the is also CH3CH23CH22Br CH3 CH3 the solventnucleophile is also EssentiallyCH no 3reactionCH2CH with2Br H2O A CH3 A CH3 at room temperature the nucleophile Essentially no reaction with H2O CH3CClšš A ϩ CH3šOH CH3CšOCHA 3 ϩ HClšš at room temperature CHA3šCClšš ϩSolventCHš3šOH CHAš3CšOCH3 ϩ šHClšš CHA3š Solventš CHA3š š 2-Chloro-CH3 2-Methoxy-CH3 2-methylpropane2-Chloro- 2-methylpropane2-Methoxy- 2-methylpropane 2-methylpropane 3

Relative Reactiv- The relative rates of reaction of 2-bromopropane and 2-bromo-2-methylpropane with itiesRelative of Various Reactiv- water The to give relative the corresponding rates of reaction alcohols of 2-bromopropane are shown in Table and 2-bromo-2-methylpropane 7-1 and are compared with with Table 7-1 ities of Various Table 7-1 Bromoalkanes thewater corresponding to give the rates corresponding of hydrolysis alcohols of their unbranched are shown incounterparts. Table 7-1 andAlthough are compared the process with withBromoalkanes Water givesthe thecorresponding products expected rates of hydrolysisfrom an S Nof2 theirreaction, unbranched the order counterparts. of reactivity Although is reversed the processfrom with Water gives the products expected from an S 2 reaction, the order of reactivity is reversed from Relative that found under typical SN2 conditions. Thus,N primary halides are very slow in their reac- Bromoalkane rateRelative tionsthat with found water, under secondary typical S halidesN2 conditions. are more Thus, reactive, primary and halides tertiary are halides very areslow about in their 1 mil- reac- Bromoalkane rate liontions times with as water,fast as secondary primary ones. halides are more reactive, and tertiary halides are about 1 mil- CH3Br 1 lionThese times observations as fast as primary suggest ones. that the mechanism of solvolysis of secondary and, espe- CH3Br 1 CH3CH2Br 1 cially, Thesetertiary observations haloalkanes suggestmust be thatdifferent the mechanismfrom that of of bimolecular solvolysis substitution. of secondary To and, under- espe- in solvolysis CH3CH2Br 1 cially, tertiary haloalkanes must be different from that of bimolecular substitution. To under- (CH3)2CHBr 12 in solvolysis stand the details of this transformation, we shall use the same methods that we used to study (CH3)2CHBr 12 6 Increasing reactivity stand the details of this transformation, we shall use the same methods that we used to study (CH3)3CBr 1.2 3 10 the SN2 process: kinetics, stereochemistry, and the effect of substrate structure and solvent 6 Increasing reactivity (CH3)3CBr 1.2 3 10 onthe reaction SN2 process: rates. kinetics, stereochemistry, and the effect of substrate structure and solvent on reaction rates.

H3CCH2Br H3C Br Exercise 7-1 A A A A H3CCH2Br H3C Br Exercise 7-1 A A A A Whereas compound A (shown in the margin) is completely stable in ethanol, B is rapidly converted intoWhereas another compoundcompound. A Explain. (shown in the margin) is completely stable in ethanol, B is rapidly converted A B into another compound. Explain. A B

7-2 UNIMOLECULAR NUCLEOPHILIC SUBSTITUTION 7-2 UNIMOLECULAR NUCLEOPHILIC SUBSTITUTION In this section, we shall learn about a new pathway for nucleophilic substitution. Recall that theIn S thisN2 reaction section, we shall learn about a new pathway for nucleophilic substitution. Recall that the SN2 reaction • Has second-order kinetics • Has second-order kinetics • Generates products stereospeci" cally with inversion of con" guration • Generates products stereospeci" cally with inversion of con" guration • Is fastest with halomethanes and successively slower with primary and secondary halides• Is fastest with halomethanes and successively slower with primary and secondary halides • Takes place only extremely slowly with tertiary substrates, if at all • Takes place only extremely slowly with tertiary substrates, if at all 248 CHAPTER 7 Further Reactions of Haloalkanes

2-Bromopropane is hydrolyzed similarly, albeit much more slowly, whereas 1-bromopropane, bromoethane, and bromomethane are unchanged under these conditions. ReactionR Hydrolysis of a Secondary Haloalkane

CH3 CH3 A Relatively slow A

CH3CBršš ϩ HOšOH CH3COHš ϩ HBršš Reminder A š š Aš š Nucleophile: red H H Electrophile: blue 2-Bromopropane 2-Propanol Leaving group: green (Isopropyl bromide) (Isopropyl alcohol)

Methyl and Primary Solvolysis also takes place in alcohol solvents. Haloalkanes: Unreactive in Solvolysis Solvolysis of 2-Chloro-2-methylpropane in Methanol Although the process gives the products expected from an SN2 reaction,CH3theBr order of reactivity is reversed from that found under typical SN2 conditions. CH3CH2Br Solvolysis—the solvent is also CH3CH2CH2Br CH CH the nucleophile 3 3 Essentially no reaction with H2O A A Primary halides are very slow in their reactions with water, secondaryat halidesroom temperatureare more CH3CClšš ϩ CH3šOH CH3CšOCH3 ϩ HClšš reactive, and tertiary halides are about 1 million times as fast as primary ones. Aš Solventš Aš š CH3 CH3 2-Chloro- 2-Methoxy- To understand the details of this transformation, kinetics, stereochemistry, the effect of 2-methylpropane 2-methylpropane substrate structure, and solvent on reaction rates will be studied. Relative Reactiv- The relative rates of reaction of 2-bromopropane and 2-bromo-2-methylpropane with ities of Various Table 7-1 water to give the corresponding alcohols are shown in Table 7-1 and are compared with Bromoalkanes the corresponding rates of hydrolysis of their unbranched counterparts. Although the process with Water gives the products expected from an SN2 reaction, the order of reactivity is reversed from Relative that found under typical SN2 conditions. Thus, primary halides are very slow in their reac- Bromoalkane rate tions with water, secondary halides are more reactive, and tertiary halides are about 1 million times as fast as primary ones. CH3Br 1 These observations suggest that the mechanism of solvolysis of secondary and, espe- CH3CH2Br 1 cially, tertiary haloalkanes must be different from that of bimolecular substitution. To under- in solvolysis (CH3)2CHBr 12 stand the details of this transformation, we shall use the same methods that we used to study

6 Increasing reactivity (CH3)3CBr 1.2 3 10 the SN2 process: kinetics, stereochemistry, and the effect of substrate structure and solvent on reaction rates. 4

H3CCH2Br H3C Br Exercise 7-1 A A A A Whereas compound A (shown in the margin) is completely stable in ethanol, B is rapidly converted into another compound. Explain. A B

7-2 UNIMOLECULAR NUCLEOPHILIC SUBSTITUTION

In this section, we shall learn about a new pathway for nucleophilic substitution. Recall that the SN2 reaction • Has second-order kinetics • Generates products stereospeci" cally with inversion of con" guration • Is fastest with halomethanes and successively slower with primary and secondary halides • Takes place only extremely slowly with tertiary substrates, if at all 7.2 UNIMOLECULAR NUCLEOPHILIC SUBSTITUTION

The SN2 reaction:

• has second-order kinetics • generates products stereospecifically with inversion of configuration • is fastest with halomethanes and successively slower with primary and secondary halides • takes place only extremely slowly with tertiary substrates

In contrast, solvolysis:

• follow a first-order rate law • are not stereospecific • are characterized by the opposite order of reactivity

5 7-2 Unimolecular Nucleophilic Substitution CHAPTER 7 249

In contrast, solvolyses • Follow a ! rst-order rate law • Are not stereospeci! c • Are characterized by the opposite order of reactivity Let us see how these ! ndings can be accommodated mechanistically. Solvolysis follows ﬁ rst-order kinetics In Chapter 6, the kinetics of reaction between halomethanes and nucleophiles revealed a Solvolysisbimolecularfollows transitionfirst state:-order The kineticsrate of the SN2 reaction is proportional to the concentration of both ingredients. Similar studies have been carried out by varying the concentrations of By2-bromo-2-methylpropanevarying the concentrations and waterof 2-bromo in formic-2-methylpropane acid (a polar solventand water of veryin lowformic nucleophi-acid (a polar solventlicity) andof very measuringlow nucleophilicity) the rates of solvolysis.and measuring The resultsthe ratesof theseof experimentssolvolysis: show that the rate of hydrolysis of the bromide is proportional to the concentration of only the starting Thehalide,results not theof water.these experiments show that the rate of hydrolysis of the bromide is proportional to the concentration of only the starting halide, not the water.

21 21 Rate 5 k[(CH3)3CBr] mol L s

The observed rate is that of the slowest step in the sequence: the rate-determining step. What does this observation mean? First, it is clear that the haloalkane has to undergo Thesomemechanism transformationof solvolysison its own beforeincludes anythingcarbocation else takesformation place. Second, because the ! nal product contains a hydroxy group, water (or, in general, any nucleophile) must enter the Thereaction,hydrolysis but at a oflater2 -stagebromo and-2 -notmethylpropane in a way that iswillsaid affectto theproceed rate law. Theby onlyunimolecular way to explain this behavior is to postulate that any steps that follow the initial reaction of the nucleophilic substitution, abbreviated SN1. The number 1 indicates that only one moleculehalide areparticipates relatively fast.in the In rate other-determining words, the observedstep: The raterate isof thatthe ofreaction the slowestdoes stepnot depend in onthethe sequence:concentration the rate-determiningof the nucleophile step.. It follows that only those species taking part in the transition state of this step enter into the rate expression: in this case, only the starting haloalkane. 6 In analogy, think of the rate-determining step as a bottleneck. Imagine a water hose with several attached clamps restricting the " ow (Figure 7-1). We can see that the rate at which the water will spew out of the end is controlled by the narrowest constriction. If we were to reverse the direction of " ow (to model the reversibility of a reaction), again the rate of " ow would be controlled by this point. Such is the case in transformations consist- ing of more than one step—for example, solvolysis. What, then, are the steps in our example?

Constriction

Water Water k flow flow Figure 7-1 The rate k at which water ! ows through this hose is controlled by the narrowest Rate determining constriction.

The mechanism of solvolysis includes carbocation formation The hydrolysis of 2-bromo-2-methylpropane is said to proceed by unimolecular nucleophilic substitution, abbreviated SN1. The number 1 indicates that only one molecule, the haloalkane, participates in the rate-determining step: The rate of the reaction does not depend Mechanism on the concentration of the nucleophile. The mechanism consists of three steps. The mechanism consists of three steps.

250 StepCHAPTER1. The rate7 Further-determining Reactionsstep of isHaloalkanesthe dissociation of the haloalkane to an alkyl cation and bromide. This conversion is an example of heterolytic cleavage.

The hydrocarbonStepproduct 1. The rate-determiningcontains a steppositively is the dissociationcharged of the central haloalkane carbon to an alkyl atom cation attached to and bromide, a process we have already seen in Section 2-2. three other groups and bearing only an electron sextet. Such a structure is called a Animation carbocation. Dissociation of Halide to Form a Carbocation ANIMATED MECHANISM: CH3 CH3 Nucleophilic substitution A Rate determining A (S 1) of (CH ) CBr with HOH ϩ Ϫ N 3 3 CH3COBršš CH3C ϩ Bršš š A š A š CH3 CH3

Heterolytic cleavage of the carbon–halogen bond separates opposite charges, making this step slow and rate determining. Br Br

1,1-Dimethylethyl cation 7 (tert-Butyl cation)

This conversion is an example of heterolytic cleavage. The hydrocarbon product contains a positively charged central carbon atom attached to three other groups and bearing only an electron sextet. Such a structure is called a carbocation. The terms “trap” or “capture” describe the fast attack on a Step 2. The 1,1-dimethylethyl (tert-butyl) cation formed in step 1 is a powerful electrophile reactive intermediate by that is immediately trapped by the surrounding water. This process can be viewed as a another chemical species. nucleophilic attack by the solvent on the electron-de" cient carbon.

Nucleophilic Attack by Water

CH3 H CH3 H A Fast A ϩš ϩ f f CH3C ϩ Oš CH3COO A š i A i CH3 H CH3 H

ϩ ROHOO"š ϩ H

OO H f ROOšϩ i H Alkyloxonium ion An alkyloxonium ion

The resulting species is an example of an alkyloxonium ion, the conjugate acid of an alcohol—in this case 2-methyl-2-propanol, the eventual product of the sequence.

1 Step 3. Like the hydronium ion, H3O , the " rst member of the series of oxonium ions,* all alkyloxonium ions are strong acids. They are therefore readily deprotonated by the water in the reaction medium to furnish the " nal alcohol.

1 *Indeed, IUPAC recommends the use of the name oxonium ion instead of hydronium ion for H3O . 250 CHAPTER 7 Further Reactions of Haloalkanes

250 CHAPTER 7 FurtherStep 1. The Reactions rate-determining of Haloalkanes step is the dissociation of the haloalkane to an alkyl cation and bromide, a process we have already seen in Section 2-2. Animation Step 1. The rate-determiningDissociation step isof theHalide dissociation to Form a of Carbocation the haloalkane to an alkyl cation ANIMATED MECHANISM: and bromide, a process we have already seen in Section 2-2. Nucleophilic substitution CH3 CH3 Animation A Rate determining A (S 1) of (CH ) CBr with HOH ϩ Ϫ N 3 3 DissociationCH3COBršš of Halide to FormCH a Carbocation3C ϩ Bršš š ANIMATED MECHANISM: A š A š CHCH33 CHCH33 Nucleophilic substitution A Rate determining A (S 1) of (CH ) CBr with HOH ϩ Ϫ N 3 3 CH3COBršš CH3C ϩ Bršš š Heterolytic cleavage of the A A carbon–halogen bond š š CH3 CH3 separates opposite charges, making this step slow and Heterolyticrate determining. cleavage of the carbon–halogen bond Br Br separates opposite charges, making this step slow and rate determining. Br Br 1,1-Dimethylethyl cation (tert-Butyl cation)

This conversion is an example of heterolytic cleavage.1,1-Dimethylethyl The hydrocarbon product contains cation a positively charged central carbon atom attached (totert three-Butyl othercation) groups and bearing only an electron sextet. Such a structure is called a carbocation. The terms “trap” or “capture” Stepdescribe2. The the fast1 attack,1-dimethylethyl on a ThisStep conversion (2.tert The-butyl) 1,1-dimethylethyl is ancation example formed(oftert heterolytic-butyl) incation stepcleavage. formed1 isThe in astep hydrocarbonpowerful 1 is a powerful productelectrophile electrophile contains thatreactiveis immediately intermediate by trappedathat positivelyby is the immediately chargedsurrounding central trapped carbon by water the atom surrounding. Thisattached process water. to three This other can process groupsbe can andviewed be bearing viewedas only as aa another chemical species. an electron sextet. Such a structure is called a carbocation. nucleophilicThe terms “trap”attack or “capture”by the solvent nucleophilicon attackthe electronby the solvent-deficient on the electron-decarbon" cient. carbon. describe the fast attack on a Step 2. The 1,1-dimethylethyl (tert-butyl) cation formed in step 1 is a powerful electrophile reactive intermediate by that is immediately trapped byNucleophilic the surrounding Attack water. by Water This process can be viewed as a Theanotherresulting chemical species.species is an example of an alkyloxonium ion, the conjugate acid of an nucleophilic attack by the solventCH on3 the electron-deH " cientCH carbon.3 H alcohol—in this case 2-methyl-2-propanol, the eventualA productFast of theA sequence. ϩš ϩ f f CH3C ϩ Oš CH3COO NucleophilicA š i Attack by WaterA i CH3 H CH3 H CH3 H CH3 H A Fast A ϩš ϩ f f CH3C ϩ Oš CH3COO A š i A i ϩ CH H CH H ROHOO"š ϩ H 3 3

OO ROHOOš ϩHHϩ " f ROOšϩ i H OO AlkyloxoniumH ion An alkyloxonium ion f ROOšϩ i The resulting species is an example of an alkyloxonium ion, the conjugate acid of an H alcohol—in this case 2-methyl-2-propanol, the eventual product of the sequence. Alkyloxonium ion An alkyloxonium ion 8 1 Step 3. Like the hydronium ion, H3O , the " rst member of the series of oxonium ions,* Theall alkyloxonium resulting species ions are is anstrong example acids. of They an arealkyloxonium therefore readily ion, deprotonatedthe conjugate by acid the ofwater an alcohol—inin the reaction this medium case 2-methyl-2-propanol, to furnish the " nal alcohol. the eventual product of the sequence.

1 Step 3. Like the hydronium ion, H3O , the " rst member of the series of oxonium ions,* all alkyloxonium ions are strong acids. They are therefore readily deprotonated by the water *Indeed, IUPAC recommends the use of the name oxonium ion instead of hydronium ion for H O1. in the reaction medium to furnish the " nal alcohol. 3

1 *Indeed, IUPAC recommends the use of the name oxonium ion instead of hydronium ion for H3O . + Step 3. Like the hydronium ion, H3O , the first member of the series of oxonium ions, all alkyloxonium ions are strong acids. They7-2 Unimolecularare therefore Nucleophilicreadily deprotonated Substitutionby theCHAPTERwater in 7 251 the reaction medium to furnish the final alcohol.

Deprotonation

CH3 H CH3 A Fast A ϩ ϩ f CH3COOð ϩ #šOH2 CH3C##šOH ϩ HOH2 A i A CH3 H CH3

O O O O

Alkyloxonium ion 2-Methyl-2-propanol (Strongly acidic)

Figure 7-2 compares the potential-energy diagrams for the S 2 reaction of chloromethane N 9 with hydroxide ion and the SN1 reaction of 2-bromo-2-methylpropane with water. The SN1 diagram exhibits three transition states, one for each step in the mechanism. The ! rst has the highest energy—and thus is rate determining—because it requires the separation of opposite charges.

Exercise 7-2 Using the bond-strength data in Table 3-1, calculate the DH8 for the hydrolysis of 2-bromo- 2-methylpropane to 2-methyl-2-propanol and hydrogen bromide. [Caution: Don’t get confused by the ionic mechanism of these reactions. The DH8 is a measure of the thermicity of the overall transformation, regardless of mechanism (Section 2-1).]

SN2: One Step SN1: Three Steps H ‡ ‡ H3C δ − δ − + − HO C Cl } Cδ Xδ @ H3C HH H3C + (CH3)3C transition state

E E Rate-determining Only one transition state CH Cl (CH3)3CBr 3 HOH H + −OH + + (CH3)3CO (CH3)3COH H HBr CH3OH + + Cl−

Reaction coordinate Reaction coordinate A B

Figure 7-2 Potential-energy diagrams for (A) SN2 reaction of chloromethane with hydroxide and (B) SN1 hydrolysis of 2-bromo-2-methylpropane. Whereas the SN2 process takes place in a single Animation step, the SN1 mechanism consists of three distinct events: rate-determining dissociation of the haloalkane into a halide ion and a carbocation, nucleophilic attack by water on the carbocation to give an alkyloxonium ion, and proton loss to furnish the ! nal product. Note: For clarity, inorganic ANIMATED MECHANISM: Nucleophilic species have been omitted from the intermediate stages of (B). substitution (SN1) of (CH3)3CBr with HOH 7-2 Unimolecular Nucleophilic Substitution CHAPTER 7 251

Deprotonation

CH3 H CH3 A Fast A ϩ ϩ f CH3COOð ϩ #šOH2 CH3C##šOH ϩ HOH2 A i A CH3 H CH3

O O O O

Alkyloxonium ion 2-Methyl-2-propanol (Strongly acidic)

Figure 7-2 compares the potential-energy diagrams for the SN2 reaction of chloromethane with hydroxide ion and the SN1 reaction of 2-bromo-2-methylpropane with water. The SN1 diagram exhibits three transition states, one for each step in the mechanism. The ! rst has the highest energy—and thus is rate determining—because it requires the separation of opposite charges.

Exercise 7-2 Using the bond-strength data in Table 3-1, calculate the DH8 for the hydrolysis of 2-bromo- 2-methylpropane to 2-methyl-2-propanol and hydrogen bromide. [Caution: Don’t get confused by The SN1 diagram exhibits three transition states, one for each step in the mechanism. The the ionic mechanism of these reactions. The DH8 is a measure of the thermicity of the overall first has thetransformation,highest regardlessenergy of mechanism—and (Sectionthus 2-1).] is rate determining—because it requires the separation of opposite charges.

SN2: One Step SN1: Three Steps H ‡ ‡ H3C δ − δ − + − HO C Cl } Cδ Xδ @ H3C HH H3C + (CH3)3C transition state

E E Rate-determining Only one transition state CH Cl (CH3)3CBr 3 HOH H + −OH + + (CH3)3CO (CH3)3COH H HBr CH3OH + + Cl−

Reaction coordinate Reaction coordinate All three steps of the mechanismA of solvolysis are reversible. TheB overall equilibrium can be driven inFigureeither 7-2direction Potential-energyby diagramsthe suitable for (A) SN2 reactionchoice of chloromethaneof reaction withconditions hydroxide and . Thus, a large excess (B) SN1 hydrolysis of 2-bromo-2-methylpropane. Whereas the SN2 process takes place in a single Animation 10 of nucleophilicstep, the SsolventN1 mechanismensures consists ofcomplete three distinct events:solvolysis rate-determining. dissociation of the haloalkane into a halide ion and a carbocation, nucleophilic attack by water on the carbocation to give an alkyloxonium ion, and proton loss to furnish the ! nal product. Note: For clarity, inorganic ANIMATED MECHANISM: Nucleophilic species have been omitted from the intermediate stages of (B). substitution (SN1) of (CH3)3CBr with HOH 252 CHAPTER 7 Further Reactions of Haloalkanes

All three steps of the mechanism of solvolysis are reversible. The overall equilibrium can be driven in either direction by the suitable choice of reaction conditions. Thus, a large excess of nucleophilic solvent ensures complete solvolysis. In Chapter 9, we shall see how this reaction can be reversed to permit the synthesis of tertiary haloalkanes from alcohols. In Summary The kinetics of haloalkane solvolysis lead us to a three-step mechanism. The crucial, rate-determining step is the initial dissociation of a leaving group from the starting material to form a carbocation. Because only the substrate molecule participates in the rate- limiting step, this process is called unimolecular nucleophilic substitution, SN1. Let us now see what other experimental observations can tell us about the SN1 mechanism.

Model Building 7-3 STEREOCHEMICAL CONSEQUENCES OF SN1 REACTIONS

The proposed mechanism of unimolecular nucleophilic substitution has predictable stereochemical consequences because of the structure of the intermediate carbocation. To mini- 7.3 STEREOCHEMICAL CONSEQUENCES OF SN1 REACTIONS mize electron repulsion, the positively charged carbon assumes trigonal planar geometry, the result of sp2 hybridization (Sections 1-3 and 1-8). Such an intermediate is therefore To minimize electronachiralrepulsion, (make a model).the Hence,positively starting with ancharged optically activecarbon secondaryassumes or tertiary halo-trigonal planar geometry,Animationthe resultalkaneof sp in2 whichhybridization the stereocenter. Such bears thean departingintermediate halogen, underis therefore conditions favorableachiral . for SN1 reaction we should obtain racemic products (Figure 7-3). This result is, in fact, ANIMATED MECHANISM: observed in many solvolyses. In general, the formation of racemic products from optically StartingNucleophilicwith substitutionan opticallyactive substratesactive is strongsecondary evidence foror the tertiaryintermediatehaloalkane being a symmetrical,in achiralwhich species,the stereocenter (SN1) of (CH3)3CBr with HOH such as a carbocation. bears the departing halogen, under conditions favorable for SN1 reaction we should obtain racemic products. This result is observed in many solvolyses. OH

H3C H + H2O (S)-1-Phenylethanol Br −HBr − C Br + H3C C + H −HBr H3C H H2O H H3C (S)-(1-Bromoethyl) benzene C Planar, achiral OH

(R)-1-Phenylethanol 11 Racemic mixture

Figure 7-3 The mechanism of hydrolysis of (S)-(1-bromoethyl)benzene explains the stereochemistry of the reaction. Initial ionization furnishes a planar, achiral carbocation. This ion, when trapped with water, yields racemic alcohol.

Exercise 7-3 (R)-3-Bromo-3-methylhexane loses its optical activity when dissolved in nitromethane, a highly polar but nonnucleophilic solvent. Explain by a detailed mechanism. (Caution: When writing mechanisms, use “arrow pushing” to depict electron ! ow; write out every step separately; formu- late complete structures, including charges and relevant electron pairs; and draw explicit reaction arrows to connect starting materials or intermediates with their respective products. Don’t use shortcuts, and don’t be sloppy!) 7.4 EFFECTS OF SOLVENT, LEAVING GROUP, AND NUCLEOPHILE ON UNIMOLECULAR SUBSTITUTION

As in SN2 reactions, varying the solvent, the leaving group, and the nucleophile greatly affects unimolecular substitution.

Polar solvents accelerate the SN1 reaction

Heterolytic cleavage of the C–X bond in the rate-determining step of the SN1 reaction entails a transition-state structure that is highly polarized, leading eventually to two fully charged ions.

In contrast, in a typical SN2 transition state, charges are not created; rather, they are dispersed.

Because of this polar transition state, the rate of an SN1 reaction increases as solvent polarity is increased.

12 254 254CHAPTER 7CHAPTERFurther 7ReactionsFurther of Reactions Haloalkanes of Haloalkanes

Polar solventsPolar accelerate solvents acceleratethe SN1 reaction the SN1 reaction

Heterolytic cleavageHeterolytic of the cleavage C–X bond of the in the C–X rate-determining bond in the rate-determining step of the SN 1 step reaction of the SN1 reaction entails a transition-stateentails a transition-statestructure that is structure highly polarizedthat is highly (Figure polarized 7-4), leading (Figure eventually 7-4), leading eventually to two fully chargedto two ions. fully In charged contrast, ions. in aIn typical contrast, SN 2in transition a typical state,SN2 transition charges are state, not charges cre- are not created; rather, theyated; are rather,dispersed they (see are Figuredispersed 6-4). (see Figure 6-4). Because of thisBecause polar transition of this polar state, transition the rate of state, an S theN1 rate reaction of an increases SN1 reaction as solvent increases as solvent polarity is increased.polarity The is increased. effect is particularly The effect striking is particularly when the striking solvent when is changed the solvent from is changed from aprotic to protic.aprotic For example, to protic. hydrolysis For example, of 2-bromo-2-methylpropane hydrolysis of 2-bromo-2-methylpropane is much faster is in much faster in pure water thanpure in a water 9:1 mixture than in of a 9:1 acetone mixture and of water. acetone The and protic water. solvent The accelerates protic solvent the accelerates the SN1 reaction becauseSN1 reaction it stabilizes because the it transition stabilizes state the transition shown in state Figure shown 7-4 byin Figure hydrogen 7-4 by hydrogen bonding with thebonding leaving with group. the leavingRemember group. that, Remember in contrast, that, the in S Ncontrast,2 reaction the is S acceler-N2 reaction is acceler- The effectatedis particularlyin polar aproticated strikingin solvents, polar aproticwhen mainly solvents,the becausesolvent mainly of a solventis becausechanged effect of a onsolventfrom the reactivity aproticeffect on oftheto the proticreactivity . For of the nucleophile. nucleophile. example, hydrolysis of 2-bromo-2-methylpropane is much faster in pure water than in a 9:1 mixture of acetone and water. Effect of SolventEffect on theof Solvent Rate of on an the SN 1Rate Reaction of an SN1 Reaction

Relative rate Relative rate 100% H2O 100% H2O (CH ) CBr (CH3)3CBr (CH ) COHϩ(CH HBr3)3COH400,000ϩ HBr 400,000 3 3 More polar solvent More polar3 3solvent

90% acetone, 10% H O90% acetone, 10% H2O (CH ) CBr (CH ) CBr 2 (CH ) COH ϩ(CHHBr) COH ϩ1 HBr 1 3 3 Less polar3 3 solvent Less polar3 solvent3 3 3

The protic solvent accelerates the SN1 reaction because it stabilizes the transition state by hydrogen bondingThe solventwith the nitromethane,Theleaving solvent group CH nitromethane,3NO.2 (see Table CH3NO 6-5),2 (see is bothTable highly 6-5), ispolar both and highly virtually polar and virtually nonnucleophilic.nonnucleophilic. Therefore, it is Therefore,useful in studiesit is useful of S Nin1 studiesreactions of withSN1 nucleophilesreactions with other nucleophiles other than solvent molecules.than solvent molecules. In contrast, the SN2 reaction is accelerated in polar aprotic solvents, mainly because of a solvent effect on the reactivity of the nucleophile.

‡‡‡‡ G A G A A A

A A

ϩ Ϫ ϩ Ϫ Ϫ Ϫ Ϫ Ϫ

C Figure 7-4 TheFigure respective 7-4 tran- The respective tran- C ␦ ␦ C␦ ␦ X␦ Nu␦ ␦ C X␦ sition states for the S 1 and S 2 C X Nu C X sition states for the SN1 and SN2 N N B ( B ( 0 ≥ 0 ≥ reactions explain reactionswhy the SexplainN1 pro- why the SN1 pro- C C B C B C cess is strongly acceleratedcess is strongly by accelerated by S 1 S 2 polar solvents. Heterolyticpolar solvents. cleav- Heterolytic cleav- SN1 N SN2 N age entails chargeage separation, entails charge a separation, a Opposite charges Opposite chargesNegative charge Negative charge 13 process aided byprocess polar solvation. aided by polar solvation. are separated are separated is dispersed is dispersed

The SN1 reactionThe SN speeds1 reaction up withspeeds better up with leaving better groups leaving groups

Because the leavingBecause group the departs leaving in group the rate-determining departs in the rate-determining step of the SN1 stepreaction, of the it S isN1 not reaction, it is not surprising that thesurprising rate of thethat reaction the rate increasesof the reaction as the increases leaving-group as the abilityleaving-group of the departing ability of the departing group improves.group Thus, improves. tertiary iodoalkanes Thus, tertiary more iodoalkanes readily undergo more readily solvolysis undergo than solvolysis do the than do the corresponding bromides,corresponding and bromidesbromides, are, and in bromides turn, more are, reactive in turn, than more chlorides. reactive thanSulfonates chlorides. Sulfonates are particularly areprone particularly to departure. prone to departure.

Relative Rate ofRelative Solvolysis Rate of of RX Solvolysis (R 5 Tertiary of RX (R Alkyl) 5 Tertiary Alkyl)

X 5 O OSO2RX9 .5 OO I OSO . O2R Br9 .. OO I Cl . O Br . O Cl

Increasing rateIncreasing rate

The strengthThe of strength the nucleophile of the nucleophile affects the affects product the distribution product distribution but not thebut reaction not the rate reaction rate

Does changing Does the nucleophile changing the affect nucleophile the rate affectof SN 1 the reaction? rate of The SN1 answer reaction? is The no. Recall answer is no. Recall that, in the SN2 that,process, in the the S Nrate2 process, of reaction the rateincreases of reaction signi !increases cantly as signithe nucleophilicity! cantly as the nucleophilicityof of the attacking speciesthe attacking improves. species However, improves. because However, the rate-determining because the rate-determining step of unimolecu- step of unimolecular substitution lar does substitution not include does the not nucleophile, include the changing nucleophile, its structure changing (or its concentration) structure (or concentration) 254 CHAPTER 7 Further Reactions of Haloalkanes

Polar solvents accelerate the SN1 reaction

Heterolytic cleavage of the C–X bond in the rate-determining step of the SN1 reaction entails a transition-state structure that is highly polarized (Figure 7-4), leading eventually to two fully charged ions. In contrast, in a typical SN2 transition state, charges are not created; rather, they are dispersed (see Figure 6-4). Because of this polar transition state, the rate of an SN1 reaction increases as solvent polarity is increased. The effect is particularly striking when the solvent is changed from aprotic to protic. For example, hydrolysis of 2-bromo-2-methylpropane is much faster in pure water than in a 9:1 mixture of acetone and water. The protic solvent accelerates the SN1 reaction because it stabilizes the transition state shown in Figure 7-4 by hydrogen bonding with the leaving group. Remember that, in contrast, the SN2 reaction is accelerated in polar aprotic solvents, mainly because of a solvent effect on the reactivity of the nucleophile.

Effect of Solvent on the Rate of an SN1 Reaction

Relative rate 100% H O (CH ) CBr 2 (CH ) COHϩ HBr 400,000 3 3 More polar solvent 3 3

90% acetone, 10% H O (CH ) CBr 2 (CH ) COH ϩ HBr 1 3 3 Less polar solvent 3 3

The solvent nitromethane, CH3NO2 (see Table 6-5), is both highly polar and virtually nonnucleophilic. Therefore, it is useful in studies of SN1 reactions with nucleophiles other than solvent molecules.

‡‡ A G A A

ϩ Ϫ Ϫ Ϫ Figure 7-4 The respective tran- C C␦ X␦ Nu␦ C X␦ sition states for the SN1 and SN2 B ( 0 ≥ reactions explain why the SN1 pro- C B C cess is strongly accelerated by polar solvents. Heterolytic cleav- SN1 SN2 age entails charge separation, a Opposite charges Negative charge process aided by polar solvation. are separated is dispersed

The SN1 reaction speeds up with better leaving groups The SN1 reaction speeds up with better leaving groups Because the leaving group departs in the rate-determining step of the SN1 reaction, it is not Because the leaving group departs in the rate-determining step of the SN1 reaction, it is not surprising thatsurprisingthe rate that theof therate ofreaction the reactionincreases increases asas thethe leaving-groupleaving- groupability ofability the departingof the departing group improvesgroup. improves. Thus, tertiary iodoalkanes more readily undergo solvolysis than do the corresponding bromides, and bromides are, in turn, more reactive than chlorides. Sulfonates Tertiary iodoalkanesare particularlymore pronereadily to departure.undergo solvolysis than do the corresponding bromides, and bromides are more reactive than chlorides. Sulfonates are particularly prone to departure. Relative Rate of Solvolysis of RX (R 5 Tertiary Alkyl)

X 5 O OSO2R9 . O I . O Br . O Cl

Increasing rate

The strength of the nucleophile affects the product distribution but not the reaction rate The strength of the nucleophile affects the product distribution but not the reaction rate

Because theDoesrate changing-determining the nucleophilestep affectof theunimolecular rate of SN1 reaction?substitution The answerdoes is no. not Recallinclude the nucleophile,that,changing in the SN2 process,its structure the rate of reaction(or concentration) increases signi! cantlydoes as the nucleophilicitynot alter theof rate of disappearancethe attackingof the haloalkanespecies improves.. However, because the rate-determining step of unimolecular substitution does not include the nucleophile, changing its structure (or concentration) When two or more nucleophiles compete for capture of the intermediate carbocation, their relative strengths and concentrations may greatly affect the product distribution. 14 7-4 Effects on Unimolecular Substitution CHAPTER 7 255

does not alter the rate of disappearance of the haloalkane. Nevertheless, when two or more nucleophiles compete for capture of the intermediate carbocation, their relative strengths and concentrations may greatly affect the product distribution. For example, hydrolysisFor example, ofhydrolysisa solution of a solutionof 2-chloro of 2-chloro-2-methylpropane-2-methylpropane givesgives thethe expectedexpected 2- methyl-2-propanol2-methyl-2-propanol(tert-butyl (tertalcohol),-butyl alcohol),with witha rate a rateconstant constant k1k. 1Quite. Quite a differenta different result is result is obtained whenobtainedthe whensame the experimentsame experimentis iscarried carried outout in thein thepresencepresence of the solubleof the salt solublecal- salt calcium formatecium. formate: 1,1-Dimethylethyl formate (tert-butyl formate) replaces the alcohol as the product, but the reaction still proceeds at exactly the same rate k1. In this case, formate Formate ion,ion,a abetter better nucleophilenucleophile thanthan water,water, wins outwins in competitionout in competition for bonding to forthe bondinginterme- to the diate carbocation. The rate of disappearance of the starting material is determined by k1 intermediate(regardlesscarbocation of the. productThe rate eventuallyof disappearance formed), but the relativeof the yieldsstarting of thematerial products dependis determined by k1, but theon therelative relative reactivitiesyields of andthe concentrationsproducts ofdepend the competingon thenucleophiles.relative reactivities and concentrations of the competing nucleophiles.

Competing Nucleophiles in the SN1 Reaction

(CH3)3COH ϩ HCl 2-Methyl-2-propanol (CH3)3CCl O H 2 ϩ k 1 ϩ Ϫ Water and formate ion compete for cation HOH (CH3)3C ϩ Cl O Rate determining Ϫ OCH ϩ O O

1 1 ⁄2 Ca(OCH)2 (CH3)3COCH ϩ ⁄2 CaCl2 Calcium 1,1-Dimethylethyl formate formate 15 (tert-Butyl formate)

Solved Exercise 7-6 Working with the Concepts: Nucleophile Competition A solution of 1,1-dimethylethyl (tert-butyl) methanesulfonate in polar aprotic solvent containing equal amounts of sodium " uoride and sodium bromide produces 75% 2-" uoro-2-methylpropane Note: The word “Explain” in and only 25% 2-bromo-2-methylpropane. Explain. (Hint: Refer to Section 6-8 and Problem 58 of a problem usually means that Chapter 6 for information regarding relative nucleophilic strengths of the halide ions in aprotic you need to think about the solvents.) mechanism in order to ! nd a solution. Strategy The substrate is tertiary; therefore, substitution can proceed readily only via the SN1 mechanism. Equal amounts of the two nucleophiles are present, but the two substitution products do not form in equivalent yields. The explanation must lie in differences in nucleophile strength and rate of carbocation trapping under the reaction conditions.

Solution • Hydrogen bonding is absent in polar aprotic solvents, so nucleophilicity is determined by polar- izability and basicity. • Bromide, the larger ion, is more polarizable, but " uoride is the stronger base (see either Table 2-2 or 6-4). Which effect wins? They are closely balanced, but the table in Problem 58 of Chapter 6 provides the answer: In DMF (Table 6-5), Cl2, the stronger base, is about twice as nucleophilic as Br2. Fluoride is even more basic; consequently, it wins out over other halide ions in attacking the carbocation intermediate.

Exercise 7-7 Try It Yourself Predict the major substitution product that would result from mixing 2-bromo-2-methylpropane with concentrated aqueous ammonia. (Caution: Although ammonia in water forms ammonium 1 2 hydroxide according to the equation NH3 1 H2O st NH4 OH, the Keq for this process is very small. Thus the concentration of hydroxide is quite low.) 256 CHAPTER 7 Further Reactions of Haloalkanes

In Summary We have seen further evidence supporting the SN1 mechanism for the reaction of tertiary (and secondary) haloalkanes with certain nucleophiles. The stereochemistry of the process, the effects of the solvent and the leaving-group ability on the rate, and the absence of such effects when the strength of the nucleophile is varied, are consistent with the unimolecular route.

7-5 EFFECT OF THE ALKYL GROUP ON THE SN1 REACTION: CARBOCATION STABILITY

What is so special about tertiary haloalkanes that they undergo conversion by the SN1 7.5 EFFECTpathway,OF whereasTHE primaryALKYL systemsGROUP follow SNON2? HowTHE do secondaryS 1 REACTION haloalkanes :! t intoCARBOCATION this scheme? Somehow, the degree of substitution at the reactingN carbon must control the path- STABILITYway followed in the reaction of haloalkanes (and related derivatives) with nucleophiles. We shall see that only secondary and tertiary systems can form carbocations. For this reason, Carbocation stability increases from primary to secondary to tertiary tertiary halides, whose steric bulk inhibits them from undergoing SN2 reactions, substitute Primary haloalkanesalmost exclusivelyundergo by the SN1 onlymechanism,bimolecular primary haloalkanesnucleophilic only by substitutionSN2, and secondary. In contrast, haloalkanes by either route, depending on conditions. secondary and tertiary systems often transform through carbocation intermediates. The reasonsCarbocationfor this difference stability: (increases1) steric hindrance from primaryincreases to secondaryalong the series, thereby to tertiary slowing down SN2 and (2) increasing alkyl substitution stabilizes carbocation centers. We have learned that primary haloalkanes undergo only bimolecular nucleophilic substitu- Only secondarytion. In andcontrast,tertiary secondarycations systemsare oftenenergetically transform throughfeasible carbocationunder theintermediatesconditions and of the SN1 reaction. tertiary systems virtually always do. The reasons for this difference are twofold. First, steric hindrance increases along the series, thereby slowing down SN2. Second, increasing alkyl Tertiary haloalkanessubstitution stabilizesundergo carbocationsolvolysis centers.so readily, Only secondarybecause and tertiary tertiary cationscarbocations are ener- are more stable thangeticallytheir lessfeasiblesubstituted under the conditionsrelatives, of whichthe SN1 formreaction.more easily. Relative Stability of Carbocations ϩ ϩ ϩ CH3CH2CH2CH2 Ͻ CH3CH2CHCH3 Ͻ (CH3)3C Primary , Secondary , Tertiary

Increasing carbocation stability 16

Now we can see why tertiary haloalkanes undergo solvolysis so readily. Because tertiary carbocations are more stable than their less substituted relatives, they form more easily. But what is the reason for this order of stability? Hyperconjugation stabilizes positive charge Note that the order of carbocation stability parallels that of the corresponding radicals. Both trends have their roots in the same phenomenon: hyperconjugation. Recall from Section 3-2 that hyperconjugation is the result of overlap of a p orbital with a neighboring bonding molecular orbital, such as that of a C–H or a C–C bond. In a radical, the p orbital is singly ! lled; in a carbocation, it is empty. In both cases, the alkyl group donates electron density to the electron-de! cient center and thus stabilizes it. Figure 7-5 compares the orbital pictures of the methyl and 1,1-dimethylethyl (tert-butyl) cations and depicts the electrostatic potential maps of the methyl, ethyl, 1-methylethyl (isopropyl), and 1,1-dimethylethyl cations. Figure 7-6 shows the structure of the tertiary butyl system, which is stabilized enough to be isolated and characterized by X-ray diffraction measurements.

Secondary systems undergo both SN1 and SN2 reactions As you will have gathered from the preceding discussion, secondary haloalkanes exhibit the most varied substitution behavior. Both SN2 and SN1 reactions are possible: Steric hindrance slows but does not preclude bimolecular nucleophilic attack. At the same time, unimolecular dissociation becomes competitive because of the relative stability of secondary Hyperconjugation stabilizes positive charge Carbocation stability parallels that of the corresponding radicals. Hyperconjugation is the result of overlap of a p orbital with a neighboring bonding molecular orbital, such as that of a C–H or a C–C bond.

In a carbocation, the p orbital is empty. The7-5alkyl Effectgroup of the Alkyldonates Group onelectron the SN 1 Reactiondensity CHAPTERto the 7 257 electron-deficient center and thus stabilizes it. ++Figure 7-5 (A) The partial orbital Hyperconjugation picture of the methyl cation re- H veals why it cannot be stabilized H by hyperconjugation. (B) In contrast, the 1,1-dimethylethyl (tert- H H butyl) cation bene! ts from three C H hyperconjugative interactions. H2C The electrostatic potential maps H C C of the (C) methyl, (D) ethyl, (E) 1- methylethyl (isopropyl), and H H2C (F) 1,1- dimethylethyl (tert-butyl) H cations show how the initially strongly electron-de! cient (blue) Methyl cation 1, 1-Dimethylethyl cation central carbon increasingly loses A B (tert-Butyl cation) its blue color along the series because of increasing Secondary systems undergo both SN1 and SN2 reactions depending on conditionshyperconjugation.

Both SN2 and SN1 reactions are possible: Steric hindrance slows but does not preclude bimolecular nucleophilic attack. At the same time, unimolecular dissociation becomes competitive because of the relative stability of secondary carbocations. 17

C D E F 120° carbocations. The pathway chosen depends on the reaction conditions: the solvent, the leaving group, and the nucleophile. 1.44 Å If we use a substrate carrying a very good leaving group, a poor nucleophile, and a polar protic solvent (SN1 conditions), then unimolecular substitution is favored. If we employ a high concentration of a good nucleophile, a polar aprotic solvent, and a haloalkane bearing a reasonable leaving group (SN2 conditions), then bimolecular substitution predominates. Table 7-2 summarizes our observations regarding the reactivity of haloalkanes Figure 7-6 X-ray crystal struc- toward nucleophiles. ture determination for the 1,1- dimethylethyl (tert-butyl) cation. The four carbons lie in a plane Substitution of a Secondary Substrate Under SN1 Conditions with 1208 C – C – C bond angles,

consistent with sp2 hybridization

Oš š G H C G H C

3 B 3 at the central carbon. The C – C H2šO

C C COšOSCF3 š COOšH ϩ CF3SO3H bond length is 1.44 Å, shorter than normal single bonds (1.54 Å), a H3C ( šB H3C ( š H H consequence of hyperconjugative Oš š overlap.

Substitution of a Secondary Haloalkane Under SN2 Conditions

Model Building

G H3C G CH3

Acetone C C Ϫ Ϫ

COBršš ϩ CH3š S CH3šSOC ϩš Bršš H3C ( š š š ( CH3 š H H

2 2 Table 7-2 Reactivity of R – X in Nucleophilic Substitutions: R – X 1 Nu ¡ R–Nu 1 X

R SN1 SN2

CH3 Not observed in solution (methyl cation Frequent; fast with good nucleophiles and good leaving too high in energy) groups Primary Not observed in solution (primary Frequent; fast with good nucleophiles and good leaving carbocations too high in energy)a groups, slow when branching at C2 is present in R

Secondary 1 better Relatively slow; best with good leaving 2 better Relatively slow; best with high concentrations of good N N

S groups in polar protic solvents S nucleophiles in polar aprotic solvents Tertiary Frequent; particularly fast in polar, protic Extremely slow solvents and with good leaving groups aExceptions are resonance-stabilized carbocations; see Chapter 14. 7-5 Effect of the Alkyl Group on the SN 1 Reaction CHAPTER 7 257

++Figure 7-5 (A) The partial orbital Hyperconjugation picture of the methyl cation re- H veals why it cannot be stabilized H by hyperconjugation. (B) In contrast, the 1,1-dimethylethyl (tert- H H butyl) cation bene! ts from three C H hyperconjugative interactions. H2C The electrostatic potential maps H C C of the (C) methyl, (D) ethyl, (E) 1- methylethyl (isopropyl), and H H2C (F) 1,1- dimethylethyl (tert-butyl) H cations show how the initially strongly electron-de! cient (blue) Methyl cation 1, 1-Dimethylethyl cation central carbon increasingly loses A B (tert-Butyl cation) its blue color along the series because of increasing hyperconjugation.

C D E F The pathway chosen depends on the reaction conditions: the solvent, the leaving group, 120° and the nucleophilecarbocations.. The pathway chosen depends on the reaction conditions: the solvent, the leaving group, and the nucleophile. 1.44 Å If we use a substrateIf we usecarrying a substratea very carryinggood a veryleaving good group, leaving group,a poor a poornucleophile, nucleophile,and anda apolar protic solventpolar(SN 1 proticconditions), solvent (SthenN1 conditions),unimolecular thensubstitution unimolecular issubstitutionfavored. is favored. If we employ a high concentration of a good nucleophile, a polar aprotic solvent, and a haloalkane If we employbearinga high a reasonableconcentration leavingof groupa good (SN2 nucleophile, conditions), thena bimolecularpolar aprotic substitutionsolvent, pre-and a haloalkane bearingdominates. aTablereasonable 7-2 summarizesleaving our observationsgroup (S regarding2 conditions), the reactivitythen of haloalkanesbimolecular Figure 7-6 X-ray crystal struc- toward nucleophiles. N ture determination for the 1,1- substitution predominates. dimethylethyl (tert-butyl) cation. The four carbons lie in a plane Substitution of a Secondary Substrate Under SN1 Conditions with 1208 C – C – C bond angles,

consistent with sp2 hybridization

Oš š G H C G H C

3 B 3 at the central carbon. The C – C H2šO

C C COšOSCF3 š COOšH ϩ CF3SO3H bond length is 1.44 Å, shorter than normal single bonds (1.54 Å), a H3C ( šB H3C ( š H H consequence of hyperconjugative Oš š overlap.

Substitution of a Secondary Haloalkane Under SN2 Conditions

Model Building

G H3C G CH3

Acetone C C Ϫ Ϫ

COBršš ϩ CH3šš S CH3šSOC ϩš Bršš H3C ( š š š ( CH3 š H H 18

2 2 Table 7-2 Reactivity of R – X in Nucleophilic Substitutions: R – X 1 Nu ¡ R–Nu 1 X

R SN1 SN2

Secondary 1 better Relatively slow; best with good leaving 2 better Relatively slow; best with high concentrations of good N N

consistent with sp2 hybridization

Oš š G H C G H C

3 B 3 at the central carbon. The C – C H2šO

C C COšOSCF3 š COOšH ϩ CF3SO3H bond length is 1.44 Å, shorter than normal single bonds (1.54 Å), a H3C ( šB H3C ( š Two conditionsH must be satisfied beforeH dissociation of a carbon–halogenconsequencebond into ionsof hyperconjugativecan Oš š occur: overlap. Substitution of a Secondary Haloalkane Under SN2 Conditions

(1) the carbon atom must be secondary or tertiary so that the carbocationMhasodelsufficient Building

G H3C G CH3

thermodynamic stability toAcetoneform C C Ϫ Ϫ

COBršš ϩ CH3šš S CH3šSOC ϩš Bršš (2) theH3reactionC ( šmust takeš place in a polarš solvent( CH3 capableš of interacting with and stabilizing H H both positive and negative ions.

2 2 Table 7-2 Reactivity of R – X in Nucleophilic Substitutions: R – X 1 Nu ¡ R–Nu 1 X

R SN1 SN2

Secondary 1 better Relatively slow; best with good leaving 2 better Relatively slow; best with high concentrations of good N N

The contrast between the stereochemical outcomes of the SN1 and SN2 mechanisms directly affects the comparative utility of the two processes in synthesis. The SN2 process is stereospecific: reaction of a single stereoisomeric substrate gives a single stereoisomeric product. In contrast, virtually all reactions that proceed via the SN1 mechanism at a stereocenter give mixtures of stereoisomers.

And it gets worse: The chemistry of carbocations, in all SN1 reactions, is complex. These species are prone to rearrangements, frequently resulting in complicated collections of products. In addition, carbocations undergo another important transformation: loss of a proton to furnish a double bond.

SN1 reactions, unlike SN2 processes, are of limited use in synthesis because they fail the first two criteria of “green” reactions: They are poor in atom efficiency and wasteful overall, because they tend to lead to mixtures of stereoisomeric substitution products and other organic compounds. SN2 is “greener.”