Nucleophilic Substitution and elimination reactions (RJP lectures 1-6)

What is the mechanism for the general SN2 reaction?

Nucleophile attacks carbon and creates bond while leaving group leaves simultaneously (making and breaking bond at the same time)

SN2 is bimolecular (relies on 2 molecular species) rate depends on concentration of substrate and nucleophile

What is the mechanism for the general SN1 reaction?

Leaving group leaves on its own forming a carbocation intermediate. Nucleophile then attacks in at carbocation to form product

SN1 is unimolecular (relies on one molecular species) — rate is independent of concentration of nucleophile

Characteristics of a nucleophile

Generally have a full or partial negative charge and a lone pair of electrons

Characteristics of a substrate

Molecule that contains the leaving group

Nucleophile tends to be attracted to an atom that bears a full or partial negative charge

Where does the nucleophile attack in from in Sn2 and what does this do to the stereochemistry of the product?

The nucleophile does a backside attack (180º from leaving group) leading to Walden Inversion (inversion of stereochemistry)

SN2 is stereospecific

Where does the nucleophile attack from in SN1 and what does this mean for the stereochemistry of the product?

The nucleophile can attack from either the front or the back because the carbocation is planar — this leads to racemic mixture of products

Rate law for SN2

rate = k[nuc][subs]

Rate law for SN1

rate = k[subs]

first step is rate determining step

What is the mechanism for the general E2 reaction

Base picks up a proton from the substrate — base take a beta hydrogen (hydrogen connected to carbon adjacent to carbon with leaving group) — electrons from that bond move to form a double bond between the two carbons, and the leaving group leaves simultaneously. Bimolecular - rate depends on concentration of substrate AND base

What is the mechanism for the general E1 reaction?

leaving group leave first on its own forming carbocation intermediate. Then base takes beta hydrogen, electrons move to form double bond between carbons. Unimolecular - rate depends ONLY on concentration of substrate

Stereochemistry of the E2 reaction

E2 reactions are favored by the substrate conformation where the leaving group and the hydrogen atom that are eliminated are anti to each other - antiperiplanar/anticoplanar

If an E2 reaction produces a mixture of E and Z diastereomers then the major product will be the one produced from the more stable anticoplanar formation

E2 will be stereospecific if there is only 1 beta hydrogen to be eliminated

Stereochemistry of the E1 reaction

E1 reactions produce a mix of E and Z products as a result of the carbocation intermediate — even if there is only 1 beta hydrogen because rotation is possible

2 reasons that SN2, SN1, E2, and E1 compete

1) They all involve a substrate containing a leaving group

2) Any species that acts as a nucleophile also has the potential to act as a base and vice versa — so we refer to it as an attacking species

• when acting as a nucleophile, the attacking species uses its lone pair to form a bond to an electron poor non-hydrogen atom

• when acting as a base, the attacking species forms a bond to a hydrogen atom

Factors that influence competition between SN2, SN1, E2, and E1

1) strength of the attacking species

2) concentration of the attacking species

3) leaving group ability

4) type of carbon bonded to the leaving group

5) solvent effects

6) heat

Do strong nucleophiles favor SN1 or SN2? How does rate of reaction change with nucleophile strength? Generalization for determining nucleophile strength

Strong nucleophiles tend to favor SN2 while weak nucleophiles tend to favor SN1

Rate of SN2 reaction increases as nucleophile strength increases - SN1 rate is essentially independent of nucleophile strength

Strong nucleophiles typically have a total -1 charge; weak nucleophiles tend to be uncharged

How to identify the best nucleophile in an SN2 reaction

The less stable anion is the better nucleophile — more stable anions can delocalize the -1 charge better and are worse nucleophiles

Base strength in E2 and E1 reactions

Rate of E2 reaction increases as base strength increases - E1 rate is essentially independent of base strength

Strong bases tend to favor E2 while weak bases tend to favor E1

Steric hindrance in E2 vs SN2 reactions

strong, bulky bases tend to favor E2 over SN2 reactions — no significant steric hindrance in a proton transfer in E2, a lot of steric hindrance in SN2 trying to approach carbon

Examples of strong, bulky bases

DBN, DBU, LDA, tert-butoxide anion, neopentoxide anion

Concentration effects

High concentration of a strong attacking species favors SN2 and E2; low concentration favors SN1 and E1 — a weak attacking species favors SN1 and E1 regardless of concentration

Leaving group ability effects

SN1 and E1 are very sensitive to leaving group ability because it must leave on its own

SN2 and E2 are not as sensitive to leaving group ability because it is assisted by the attacking species

All reactions feasible with a good leaving group — with a poor leaving group only E2 and SN2 tend to be feasible

General characteristic of a good leaving group

Good leaving groups are the conjugate bases of strong acids (weak bases) — can stabilize -charge

Examples of unsuitable vs poor vs good leaving groups

Unsuitable: OH^-, RO^-, NH₂^-

Poor: F^-, RCO₂^-

Good: Cl^-, Br^-, H₂O, MsO^-, TsO^-, TfO^-

Converting a poor leaving group to a good one

Acid conditions allow a reaction to take place with an otherwise unsuitable leaving group (ex OH-)

Proton transfer step converts OH to H₂O, which is a good leaving group

R—OH + HBr —→ ?

conc. HBr facilitates a reaction to form alkyl bromide

1: proton transfer to make H2O LG

2: Br- attacks back in in SN2 reaction

RCOH + SOCl₂—→ ?

Two sequential SN2 reactions, one at sulfur, the other at carbon — alcohol first acts as nucleophile on thionyl chloride — forms alkyl chloride R—-X

Alcohols as leaving groups

Require acidic conditions for reaction to proceed

Hybridization of carbon bonded to leaving group

Substitution and elimination reactions generally do not occur unless the carbon bonded to the leaving group is sp3 hybridized

Effect of alkyl groups on substitution and elimination reactions

SN2 reactions do not take place for tertiary substrates — steric hindrance is too great

SN1 and E1 do not take place for methyl substrates and most primary substrates — carbocation intermediates are excessively unstable

As the number of alkyl groups on the carbon atom increases, the rate of SN2 reaction sharply decreases while the rate of SN1 reaction sharply increases

E2 reactions are relatively insensitive to the number of alkyl groups on the carbon bonded to the leaving group - can occur with primary, secondary, or tertiary carbons, just not methyl substrates

** but if the LG is bonded to a primary allyl or benzyl carbon, SN1 and SN2 can take place because the primary carbocation is resonance stabilized

Temperature effects on competition

Higher temperatures tend to favor elimination

Tiebreaker for SN1 and E1 reactions

Determine whether heat is added — E1 is favored if heat is added, SN1 is favored in the absence of heat

Tiebreaker for SN2 and E2 reactions

Determine whether the attacking species acts better as a base or a nucleophile - if it is bulky, the attacking species acts better as a base and favors E2, otherwise, both are favored

Steps to predict the outcome of SN1/SN2/E1/E2 competition

1) Determine whether competition is feasible

2) Rule out reactions that are unfeasible

3) Consider the attacking species - which of the remaining reactions are favored by the attacking species

4) Apply the appropriate tiebreaker

Williamson ether synthesis reactants and mechanism

An ether is formed through the reaction of an alkoxide ion with an alkyl halide via an SN2 reaction

Zaitsev’s rule

The major elimination product is the more highly substituted alkene product — the one produced by deprotonating the carbon atom initially attached to the fewest hydrogen atoms

Hofmann product

The product formed in an E2 reaction exhibiting anti-Zaitsev regiochemistry as a result of a strong bulky base

The major product will be the less highly substituted alkene

Which is the kinetic product and which is the thermodynamic product in an E2 reaction?

Kinetic product is less highly substituted alkene (Anti- Zaitsev), thermodynamic product is more highly substituted alkene (Zaitsev)

Rules to reasonably incorporate proton transfer steps and carbocation rearrangements

Avoid the appearance of incompatible acids and bases: strong acids should generally NOT appear in mechanisms under basic conditions and vice versa

Proton transfer steps are fast and can be incorporated before or after other elementary steps to avoid incompatible species

Which position should a substituent be in in a chair confirmation for the faster SN2 reaction? (axial or equatorial) and why?

Axial because it leave a less hindered approach for the nucleophile

Carbocation rearrangement

Carbocations will rearrange into more stable tertiary carbocations if possible via 1,2 hydride or 1,2 methyl shifts

What product forms when there is a resonance stabilized intermediate? (elimination)

When the carbocation intermediate has resonance structures, the more highly substituted alkene will form

What position must the leaving group sit in in the chair conformation to make E2 possible? why?

Axial because the leaving group and the beta hydrogen have to sit anti (180º) from each other for the reaction to occur

Solvent effects — which solvents favor which reactions

SN1 and E1 require polar protic solvent but SN2 and E2 can occur in protic solvent

Polar aprotic solvent favors SN2 and E2