Reaction classes

• A. AdditionsA + B → C

• B. EliminationsA → B + C

• C. SubstitutionsA—B + C—D → A—C + B—D

• D. RearrangementsA → B

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Nucleophilic Substitution and β-Elimination Reactions

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Alkyl Halides: Substitution and Elimination • There are two particularly important reactions of alkyl halides: • Substitution involves replacing the halide with some other group:

• Elimination involves removing the halide and an adjacent hydrogen atom to yield an alkene:

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Test Yourself• Complete these nucleophilic substitution reactions

• In each reaction, show all electron pairs on both the nucleophile and the leaving group

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Nucleophilic Substitution: The SN2 Reaction • Can you predict the product and the mechanism of the following reaction:

• What would be the rate law of this reaction? (Do you remember rate laws?)

• Why is this referred to as the SN2 reaction?

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Stereochemistry of the SN2 Reaction • Can you predict the product of the following reaction (including stereochemistry)?

• Can you explain why that stereochemical result is observed for all SN2 reactions?

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Steric Effects on SN2 Reactions

• Because of the “backside attack” required for the SN2 mechanism, these reactions are quite sensitive to steric effects (“crowding”). For example:

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Nucleophiles in the SN2 Reaction

• Can you explain the relative nucleophilicity of the following nucleophiles in an SN2 reaction?

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Leaving Groups in the SN2 Reaction • What is the leaving group in an SN2 reaction?

• Can you explain the relative leaving group ability of the following leaving groups?

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Summary of Reactivity in SN2 Reactions • Mechanism:

• Stereochemistry:

• What makes for a rapid SN2 reaction?• Steric Effects:

• Nucleophilicity:

• Leaving-Group Ability:

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Effect of Solvent on SN2 Reactions

• Weaker the solvation of Nu:, lesser the energy required to remove it from its solvation shell and greater the rate of SN2 reactions

• Polar aprotic solvents solvate nucleophiles poorly as they cannot donate a hydrogen bond to an anion

Rates of an SN2 Reaction as a Function of Solvent 13

Example - Stereochemistry of SN2 Reactions• Complete these SN2 reactions, showing the configuration of each product

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Test yourself

• Which of the following is the product of the SN2 reaction between the hydroxide ion (HO–) and (R)-CH3–CHDI?

• D = 2H (deuterium)

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Elimination: The E2 Reaction • Here is an example of an E2 reaction. Can you draw a curved-arrow mechanism?

• Examine the stereochemistry of the above reaction. Why is this an example of anti-elimination?

• What transition state and product would lead to syn-elimination?

• What would be the rate law for this reaction? 16

Frontier Orbitals in the E2 Reaction • Let’s take a close look at the frontier orbitals involved in the E2 reaction. There are in fact

two important interactions:

• Note the contrast between anti- and syn-elimination:

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Test yourselfExplain the observation.

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Alkene Isomers Formed by the E2 Reaction• Many E2 reactions can give more than one possible isomer. Can you explain the

distribution of products in the following reaction?

• You may notice that the above percentages do not add to 100%. What do you suppose is the other product that emerges from the above reaction?

• The choice of base can affect the distribution of products. For example:

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E2 vs. SN2: The “GFP” Reaction Hierarchy

To help decide which reaction will predominate, apply the “GFP” (good-fair-poor) reaction hierarchy. If all else is equal, choose the reaction that is at the top of the list:

1. SN2 reactions: Require good steric interactions Good if the halide is methyl or 1°Fair if the halide is 2°Poor if the halide is 3° or if the nucleophile is very bulky (e.g. t-BuO– )

2. E2 reactions: Require a strong baseGood if the base is at least as strong as OH–

Fair if the base is between H2O and OH– in strength Poor if the base is weaker than H2O

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Examples

Determine the primary product (and identify possible secondary products

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Reactions Involving Carbocations: SN1 and E1• Consider the following reaction. Why is it unlikely that this reaction proceeded by either an

SN2 or E2 mechanism?

• Can you propose a mechanism for this reaction?Hint: the rate law for this reaction is simply: rate = k[tBuBr]

• What do you suppose is a requirement for this reaction?

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Energy Diagrams

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Effect of Solvent on SN1 Reactions

• Rate of SN1 reactions depends on the ability of the solvent to:

• Keep opposite charges separated • Stabilize both positive and negative sites by

solvation

• Polar protic solvents (formic acid, water, and methanol) are the most effective solvents

Rates of an SN1 Reaction as a Function of Solvent24

The Stereochemistry of the SN1 Reaction

• Given that the SN1 mechanism proceeds through a carbocation intermediate, what would you expect to find when you subject the following alkyl halide to SN1 conditions:

• In fact, the products are: 33% S and 67% R. How can we explain this observation?

• Can we make any generalizations about the stereochemical outcome of SN1 reactions?

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SN1 vs. E1 Reactions • In general, whenever SN1 and E1 reactions take place, a mixture of both mechanisms is

observed. Why might this be the case?

• It is often the case that higher temperatures favor elimination. For instance:

• One can ensure elimination by starting with an alcohol, instead of an alkyl halide, and treating it with concentrated sulfuric acid. Can you propose a mechanism for this reaction? Does this mechanism resemble any mechanism you have seen before?

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SN1 / E1 / SN2 / E2: The “GFP” Hierarchy Revisited

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Test Yourself Now!

• Determine the primary product and identify any secondary products for each of the following reactions:

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Test yourself - Carbocation Resonance• Write an additional resonance contributing structure for each carbocation

and state which of the two makes the greater contribution to the resonance hybrid

• Classify each additional contributing structure as a 1°, 2°, or 3° allylic cation

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Rearrangements in SN1 Mechanisms• Rearrangements are common in SN1 reactions if the carbocation intermediate

can rearrange to a more stable one.

• Write the mechanism.

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• Consider the reaction of (S)-(–)-1-iodo-2-methylbutane to produce (+)-2-methyl-1-butanol

• What is the absolute configuration of the product? 1. R2. S3. R and S (racemic mixture) 4. R and S (unequal amounts)5. There is no chiral center in the product

Test yourself

I + HO OH + I

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Test yourself

• Which of the following SN2 reactions is expected to have the highest rate?

1. Methyl bromide with water in DMSO 2. Ethyl bromide with chloride in methanol3. Ethyl bromide with hydroxide in 4. Ethyl chloride with ammonia in acetonitrile5. Methyl bromide with hydrosulfide (HS–) in HMPA

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Test yourself

• What is the main reason that polar aprotic solvents are favored over polar protic solvents for SN2 reactions?

1. Polar aprotic solvents dissolve nucleophiles more readily than polar protic solvents2. Polar aprotic solvents destabilize anions3. Polar aprotic solvents stabilize cations, including carbocations4. Polar aprotic solvents form stabilizing hydrogen bonds5. Polar aprotic solvents prevent rearrangements from occurring

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Test yourself

• What statement about the SN2 reaction of methyl bromide with hydroxide is incorrect?

1. The reaction kinetics is first-order in hydroxide2. In the transition state, the carbon is sp2 hybridized3. Absolute configuration is inverted from R to S4. The reaction is faster in HMPA than in water5. The reaction can be catalyzed by I–

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Test yourself

• Which of the following would react the fastest in the substrate substitution reaction?

CH3NH2CH3CN

?

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Test yourself

• Which electrophile will react the fastest by the SN2 mechanism with cyanide (NC–) in DMF?

1. Phenyl iodide (Ph—I)2. Vinyl tosylate (H2C=CH—OTos)3. Ethyl bromide4. Cyclohexyl bromide5. Benzyl tosylate (Ph—CH2—OTos)

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Test yourself

• Which of the following reagents is the best nucleophile for an SN2 reaction?

1. Methanol2. Methoxide3. Acetate4. Hydroxide5. Water

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Test yourself

• Which of the following options will give the fastest SN1 reaction?

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Test yourself

• In a reaction between an alkyl halide and methoxide, doubling the alkyl halide concentration doubles the rate of the reaction

• Which of the following is a reasonable conclusion?

1. The reaction is an SN2 process2. The reaction proceeds by the SN1 mechanism3. The observation indicates an E2 process4. This is a reaction with E1 mechanism5. None of the choices

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Test yourself• Which compound would serve as the best starting material for the

transformation shown below?

?NaNH2

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Test yourself

• Select the reagent and solvent combination which would result in the fastest rate of substitution (R=CH3 in all cases)

1. ROH, HMPA2. RS–, H2O3. RO–, H2O4. RS–, DMSO5. RSH, H2O

I25 oC

?

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Test yourself

• Which of the following is the best nucleophile?

1. H2O2. (CH3)3N3. (CH3)2P–

4. (CH3)2O5. CH3O–

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Test yourself

• Which set of reaction conditions represents the best way to carry out the following transformation?

1. AcOH2. NaOAc in AcOH3. NaOAc in H2O4. NaOAc in DMSO5. AcOH in HMPA

Br OAc

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Hydrolysis of Nitrogen Mustards —Participation by a Neighboring Group• Write a mechanism for the hydrolysis of the nitrogen mustard bis(2-

chloroethyl)-methylamine

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Making “Carbanion” Bases from Alkyl Halides: Grignard and Organolithium Reagents • Do you recall what the pKa of methane is? • What is the conjugate base of methane? Why might we call this a “carbanion”?

• Carbanions are just about the strongest bases we know. Why might that make it difficult to form a carbanion?

• In that case, how can we form a “carbanion”?

• What are some uses for these “carbanions”?

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Reactions of Carbenes with Alkenes

• Carbenes react with alkenes in a reaction that is highly reminiscent of the reaction of bromine with alkenes. Draw in the curved-arrow mechanisms and predict the products of each of the following:

• What structures are formed by the addition of carbenes (or carbenoids) to alkenes?

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