WWU -- Chemistry Chapter 10 Nucleophilic Substitution: The S N 1 and S N 2 Mechanisms

WWU -- Chemistry Assignment for Chapter 10 We will cover all the sections in this chapter, except Sections and 10.13

WWU -- Chemistry Problem Assignment for Chapter 10 In-Text Problems , (S N 2 react) 20 (S N 1 reaction), 21, 22, 24, 25, 26, 27, 28 End-of-Chapter Problems –

WWU -- Chemistry Sect. 10.1: Nomenclature of alkyl halides -- common names methylene chloride CH 2 Cl 2 chloroform CHCl 3 carbon tetrachlorideCCl 4

WWU -- Chemistry More common and IUPAC names isopropyl chloride (2-chloropropane) sec-butyl chloride (2-chlorobutane) isobutyl chloride (1-chloro-2-methylpropane) tert-butyl chloride (2-chloro-2-methylpropane) allyl chloride (3-chloro-1-propene) vinyl chloride (chloroethene) benzyl chloride (chloromethylbenzene) phenyl chloride (chlorobenzene)

WWU -- Chemistry Sect. 10.2: Overview of nucleophilic substitution The substitution reaction: S N 1 and S N 2 Primary halides = S N 2 Secondary halides = both mechanisms! Tertiary halides = S N 1 Leaving groups: halogens most common There are a number of different nucleophiles!!

WWU -- Chemistry Nucleophilic Substitution (S N 2)

WWU -- Chemistry Nitrogen as a nucleophile (S N 2)

WWU -- Chemistry Carbon as a nucleophile (S N 2)

WWU -- Chemistry energy Reaction coordinate  

WWU -- Chemistry The S N 1 Mechanism carbocation

WWU -- Chemistry energy Reaction coordinate      intermediate

WWU -- Chemistry Sect. 10.3: S N 2 Mechanism reaction and mechanism kinetics stereochemistry substrate structure nucleophiles leaving groups solvents

WWU -- Chemistry The S N 2 Reaction Sterically accessible compounds react by this mechanism!! Methyl group is small

WWU -- Chemistry S N 2 Mechanism: kinetics The reactions follows second order (bimolecular) kinetics Rate = k [R-Br] 1 [OH - ] 1

WWU -- Chemistry energy Reaction coordinate  

WWU -- Chemistry S N 2 Reaction: stereochemistry Inversion of configuration

WWU -- Chemistry For an S N 2 Reaction: EVERY REACTION EVENT ALWAYS LEADS TO INVERSION OF CONFIGURATION

WWU -- Chemistry S N 2 Reaction: substrate structure (Table 10-5) KI in Acetone at 25°

WWU -- Chemistry Chloromethane + Iodide as the Nucleophile I-I- Fast

WWU -- Chemistry tert-Butyl Chloride + Iodide as the Nucleophile I-I- No reaction

WWU -- Chemistry S N 2 Reaction: substrate structure Reactivity order---- fastest to slowest!

WWU -- Chemistry S N 2 Reaction: nucleophilicity

WWU -- Chemistry Predict which is more nucleophilic is more nucleophilic !

WWU -- Chemistry Relative Nucleophilicity 1) In general, stronger bases are better nucleophiles 2) However, iodide doesn’t fit that pattern (weak base, but great nucleophile!) 3) Cyanide is an excellent nucleophile because of its linear structure 4) Sulfur is better than oxygen as a nucleophile

WWU -- Chemistry S N 2 Reaction: Leaving Groups Best leaving groups leave to form weak Lewis bases. Good leaving groups: –Br, I, Cl, OTs, OH 2 + “Lousy” leaving groups: –OH, OR, NH 2,, F

WWU -- Chemistry Sulfonate Leaving Groups

WWU -- Chemistry Tosylate leaving group

WWU -- Chemistry Inversion of Configuration

WWU -- Chemistry S N 2 Reaction: solvents S N 2 reactions are accelerated in polar, aprotic solvents. Consider Na + - OEt as an example of a nucleophile. Why are reactions accelerated? The Na + cation is complexed by the negative part of the aprotic solvent molecule pulling it away from – OEt. Now that the sodium ion is complexed, the oxygen in the nucleophile – OEt is more available for attack.

WWU -- Chemistry Aprotic solvents These solvents do not have OH bonds in them. They complex the cation through the lone pairs on oxygen or nitrogen:

WWU -- Chemistry How cations are complexed with aprotic solvents

WWU -- Chemistry Now that the Na + is complexed, the – OEt can react more easily

WWU -- Chemistry S N 2 Reaction: solvents S N 2 reactions are retarded (slowed) in polar, protic solvents. Protic solvents have O-H groups. Why are reactions retarded? Nucleophile is hydrogen bonded to solvent!

WWU -- Chemistry Protic solvents Typical protic solvents: abbreviations

WWU -- Chemistry Sect. 10.4: S N 1 Mechanism reaction and mechanism kinetics stereochemistry substrate structure nucleophiles leaving groups solvents

WWU -- Chemistry Solvolysis of tert-Butyl Bromide Acetone is used to dissolve everything! Water is the solvent and nucleophile (solvolysis).

WWU -- Chemistry The S N 1 Mechanism 1935: Hughes & Ingold carbocation

WWU -- Chemistry energy Reaction coordinate   intermediate 

WWU -- Chemistry S N 1 Reaction: kinetics The reactions follows first order (unimolecular) kinetics Rate = k [R-Br] 1

WWU -- Chemistry S N 1 Reaction: stereochemistry With chiral R-X compounds, the product will be racemic (50% of each enantiomer).

WWU -- Chemistry Stereochemistry in S N 1 reactions – racemic product

WWU -- Chemistry energy Reaction coordinate   intermediate 

WWU -- Chemistry S N 1 Reaction: substrate structure Solvolysis in water at 50°C

WWU -- Chemistry S N 1 Reaction: substrate structure tertiary>secondary>primary > methyl Primary and methyl halides are very unreactive! They don’t go by S N 1 reactions.

WWU -- Chemistry

Nucleophiles Usually S N 1 reactions are run in polar protic solvents; compounds with O-H groups. The polar protic solvent acts as BOTH nucleophile as well as the solvent. Common solvent/nucleophiles include: water, ethanol, methanol, acetic acid, and formic acid.

WWU -- Chemistry A protic solvent acts as both a solvent and nucleophile in S N 1 reactions - solvolysis: abbreviations

WWU -- Chemistry Typical solvolysis reaction Polar solvent stabilizes the carbocation! Solvent is the nucleophile

WWU -- Chemistry Leaving groups Leaving groups are the same as in S N 2 reactions: Cl, Br, I, OTs are the usual ones.

WWU -- Chemistry S N 1 Reaction: solvent polarity S N 1 solvolysis reactions go much faster in trifluoroacetic acid and water (high ionizing power). S N 1 solvolysis reactions go slower in ethanol and acetic acid (lower ionizing power). See table 10-9.

WWU -- Chemistry S N 2 versus S N 1 Reactions S N 2 versus S N 1 Reactions A primary alkyl halide or a methyl halide should react by an S N 2 process. Look for a good nucleophile, such as hydroxide, methoxide, etc. in an polar aprotic solvent. A tertiary alkyl halide should react by an S N 1 mechanism. Make sure to run the reaction under solvolysis (polar protic solvent) conditions! Don’t use strong base conditions -- it will give you nothing but E2 elimination! A secondary alkyl halide can go by either mechanism. Look at the solvent/nucleophile conditions!!

WWU -- Chemistry S N 2 versus S N 1 Reactions (continued) If the reaction medium is KI or NaI in acetone, this demands an S N 2 mechanism. If the reaction medium is AgNO 3 in ethanol, this demands an S N 1 mechanism. If the medium is basic, look for S N 2. If the medium is acidic or neutral, expect S N 1.

WWU -- Chemistry Comparison of S N 1 and S N 2 Reactions See Table on page 936. Great table!! Section 10-5: Solvent effects; been there done that!!

WWU -- Chemistry Sect. 10.6: classification tests Sodium iodide and potassium iodide in acetone are typical S N 2 reagents!! Silver nitrate in ethanol is a typical S N 1 reagent!!

WWU -- Chemistry Sect. 10.7: Special Cases Neopentyl compounds are very unreactive in S N 2 reactions.

WWU -- Chemistry Effect of  -substitution on S N 2 reactivity (Table 10-11) KI in Acetone at 25°    

WWU -- Chemistry Neopentyl Transition State C C Y Nu R1R1 R2R2 R3R3 Y R1R1 H H

WWU -- Chemistry Allylic and Benzylic compounds Allylic and benzylic compounds are especially reactive in S N 1 reactions. Even though they are primary substrates, they are more reactive most other halides! They form resonance stabilized carbocations.

WWU -- Chemistry Solvolysis Rates: S N 1 Table % Ethanol-water at 50°

WWU -- Chemistry Allylic and Benzylic compounds Allylic and benzylic compounds are especially reactive in S N 2 reactions. They are more reactive than typical primary compounds!

WWU -- Chemistry Reaction with KI in Acetone: S N 2 Table ° C

WWU -- Chemistry Vinyl and Phenyl Compounds

WWU -- Chemistry Reactivity order for S N 1

WWU -- Chemistry Reactivity order for S N 2 About same reactivity

WWU -- Chemistry Sect. 10.8: Cyclic Systems Cyclopropyl and cyclobutyl halides are very unreactive in both S N 1 and S N 2 reactions Cyclopentyl halides are more reactive than cyclohexyl halides in S N 1 and S N 2 reactions.

WWU -- Chemistry Bicyclic systems: Bredt’s Rule You can’t have p orbitals on a bridgehead position in a rigid bicyclic molecule. -- You cannot form a carbocation at a bridgehead position. --You cannot have a double bond at a bridgehead position. bridgehead

WWU -- Chemistry

Sect. 10.9: Carbocation Rearrangement a carbocation

WWU -- Chemistry A Closer Look... transition state

WWU -- Chemistry Carbocation Rearrangement

WWU -- Chemistry Carbocation Rearrangement

WWU -- Chemistry Carbocation Rearrangement

WWU -- Chemistry Carbocation Rearrangement

WWU -- Chemistry Carbocation Rearrangement

WWU -- Chemistry Carbocation Rearrangement

WWU -- Chemistry Carbocation Rearrangement

WWU -- Chemistry Carbocation Rearrangement

WWU -- Chemistry Sir Christopher Ingold Source: Michigan State University, Department of Chemistry

WWU -- Chemistry Saul Winstein Source: Michigan State University, Department of Chemistry

WWU -- Chemistry Sect Competing Reactions: Elimination -- Table Lower temperatures favor substitution; higher temperatures give more elimination. Highly branched compounds (secondary and tertiary compounds) give mostly elimination with strong bases. Weaker bases give more substitution. A basic medium favors E2; a more nucleophilic medium favors S N 2. Primary compounds give mostly substitution with non-bulky nucleophiles. A bulky base (tert-butoxide) gives elimination. Tertiary compounds should be reacted under solvolysis conditions to give substitution!!!

WWU -- Chemistry Sect : Neighboring group participation

WWU -- Chemistry Under S N 2 Conditions

WWU -- Chemistry Internal S N 2 reaction followed by an external S N 2 reaction

WWU -- Chemistry Neighboring Group Participation G: X

WWU -- Chemistry Neighboring group participation: Summary Retention of configuration Enhanced rate of reaction

WWU -- Chemistry Mustard gas Mustard gas is a substance that causes tissue blistering (a vesicant). It is highly reactive compound that combines with proteins and DNA and results in cellular changes immediately after exposure. Mustard gas was used as a chemical warfare agent in World War I by both sides.

WWU -- Chemistry Sect : Ion-pair mechanisms (skip!!) S N 1 reactions are “expected” to give a (racemic) mixture of the two enantiomers!! But, if the leaving group doesn’t get out of the way, you will get more inversion than retention, which makes it “look like” S N 2. In the extreme, you could have a carbocation give only inversion of configuration by an S N 1 mechanism!!

WWU -- Chemistry In-Class Problem For the following reaction, A)Identify the mechanism of this reaction. B)Predict the product(s) of this reaction, and identify them as major or minor, if appropriate.

WWU -- Chemistry The following table may be helpful as a review

WWU -- Chemistry Substitution versus Elimination Substitution versus Elimination SN1SN1SN2SN2E1E2 SubstrateStrong effect; reaction favored by tertiary halide Strong effect; reaction favored by methyl or primary halide Strong effect; reaction favored by tertiary halide Reactivity – primaryDoes not occurHighly favoredDoes not occurOccurs with strong base! Reactivity – tertiaryFavored when nucleophile is the solvent – solvolysis Does not occurOccurs under solvolysis conditions or with strong acids Highly favored when strong bases (OH -, OR - ) are used Reactivity – secondary Can occur in polar, protic solvents Favored by good nucleophile in polar, aprotic solvents Can occur in polar, protic solvents Favored when strong bases are used SolventVery strong effect; reaction favored by polar, protic solvents Strong effect; reaction favored by polar, aprotic solvents Very strong effect; reaction favored by polar, protic solvents Strong effect; reaction favored by polar, aprotic solvent Nucleophile/BaseWeak effect; reaction favored by good nucleophile/weak base Strong effect; reaction favored by good nucleophile/weak base Weak effect; reaction favored by weak base Strong effect; reaction favored by strong base Leaving GroupStrong effect; reaction favored by good leaving group