SN1 vs SN2 Reactions - Lecture notes 7 PDF

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Comparative information on the different types of substitution reactions...

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SN1 vs SN2 Reactions Substitution reactions have two common pathways: SN1 (Unimolecular, or 1st order Nucleophilic Substitution) and SN2 (Bimolecular, or 2nd order Nucleophilic Substitution). It is a kinetics controlled reaction because the products for SN1 or SN2 has basically comparable stability, so which one is the main reaction pathway highly depends on the activation energy (Ea) of the rate determining step (RDS). Table 1: Comparison between SN1 and SN2 Reactions SN2 Reaction order Reaction rate law Stereospecificity

# of main steps in mechanism Nucleophile Leaving group Structure of substrate

Solvent

Other possible steps

SN1

2 1 Rate = k[Substrate] Rate = k[Substrate][Nu]  Nu = nucleophile Yes: inversion of configuration No: near racemic at site of reaction Note: Chirality is inverted ONLY if the LG (chirality of other site, when existed, will and Nu has the same priority on the chiral remain, potentially produce a number of C; if they do not have the same priority, the diastereomers) chirality may or may not be inverted. 1 (concerted step involves both 2 (Loss of LG first to create C+ nucleophilic attack and loss of LG) intermediate and then nucleophilic attack) Requires strong nucleophile (stronger OK with weak nucleophile nucleophile favors SN2) Must have a good leaving group (LG; for alcohol, activation of LG is needed) 1° or 2° (structure at β position is also 2° or 3° (for 2° substrate, the structure at β important: another 2 alkyl groups at β position and nature of solvent will help position will significantly slow down the determine SN1 or SN2) reaction and neopentyl-like β will basically prevent the reaction from happening) Aprotic solvent (elevate the nucleophile Polar protic solvent (help stabilize both and make it even stronger; also make Ea nucleophile (to weaken nucleophile) and lower due to the higher energy on the C+ intermediate, making Ea lower) reactant side Activation of LG for alcohol is needed as 1. Activation of LG for alcohol is needed pre-requisite, either through proton transfer as pre-requisite; or tosylation 2. C+ rearrangement is also a possibility Up to two steps possible 3. Since S 1 commonly involve weak N

Activation of LG  Nucleophilic attack + Loss of LG

nucleophiles, which are generally neutral molecules, a proton transfer step at the end may be needed to achieve neutral product So up to 5 steps in SN1 Activation  Loss of LG  C+ rearrangement  Nucleophilic attack  Proton transfer

Sample mechanism #1: SN2 of alkyl halides

Sample mechanism #2: SN2 of alcohol (note the additional step) Sample mechanism #3: SN1 of alkyl halide (simplest) Sample mechanism #4: SN1 of alcohol (complicated) Sample Reaction coordinates or energy diagrams (Matches the sample mechanisms given) Sample Mechanism #1

Rate determining step in mechanism

Ea rational (keep in mind, Ea is key in kinetics controlled reactions)

Note: Another common way of activating OH group is through tosylation using tosyl chloride and pyridine.

Too large. See mechanism after table. Note: anytime you do SN1, you must consider if C+ rearrangement a legitimate possibility!! If rearrangement generate a more stable C+, you must consider C+ rearrangement!

Note on energy diagram: 1. The diagram must match the number of steps involved in each mechanism. 2. # of steps = # of transition states = # of Ea (or # or humps in diagram) 3. # of intermediates = # of steps -1 (the last step creates products instead) 4. Diagram must match the correct Rate-Determining-Step (RDS) for each mechanism (see below for discussion). Ea for RDS must be the largest among all steps. Sample Mechanism #2

Sample Mechanism #3

Commonly the concerted step of nucleophilic attack and loss of leaving group; proton transfer, if needed to activate the OH group, commonly has low Ea and is fast 1. SN2 does not involve higher energy C+ intermediate, so in general it has lower Ea and is faster (except for 3° substrate or high substitution at β position). 2. The more alkyl groups, the higher the Ea, making SN2 reaction more and more difficult going from 1°, 2° to 3°, making 3° substrate nearly impossible for SN2 3. Aprotic solvent lowers Ea by raising the energy of the reactant

Sample Mechanism #4

Commonly the loss of leaving group to create the high energy C+ intermediate; proton transfers, C+ rearrangement and nucleophilic attacks commonly have low Ea and are fast 1. SN1 does involve higher energy C+ intermediate, so in general it has higher Ea and is slower (except for 3° substrate) 2. More alkyl groups stabilize C+, making Ea lower and lower going from 1°, 2° to 3°, making SN1 faster and faster 3. Protic solvent lowers Ea by stabilizing the C+ intermediate

Sample SN1 mechanism (more complicated): The steps below depict the racemization and equilibrium between two alcohols at high T and acidic condition (water as solvent)

Based on the discussions from the table 1, we will have the following table to help predict the main reaction pathway and main substitution products. Table 2: Predicting SN1 and SN2 Structure Strong Nucleophile Strong Nucleophile Weak Nucleophile Weak Nucleophile of substrate Aprotic Solvent Protic Solvent Aprotic Solvent Protic Solvent 1°* SN2 (SN1 negligible) SN2 (SN1 negligible) SN2 (SN1 negligible) SN2 (SN1 negligible) 2°** SN2 SN2/ SN1 SN2/ SN1 SN1 3° SN1 (SN2 negligible) SN1 (SN2 negligible) SN1 (SN2 negligible) SN1 (SN2 negligible) * Commonly SN2 is the dominating pathway for 1° substrate. The only exception is when β position has neopentyl-like group (3 alkyl substitutions). In this case it will go through a concerted step of loss of leaving group and rearrangement before a nucleophilic attack because 1° C+ is not stable. It is both similar to and different from regular SN1 (see the first step below; nucleophilic attack step did not show):

** For 2° substrate, SN1 and SN2 are significantly competing against each other. In addition to the strength of nucleophiles and nature of solvent as impacting factors, structure at β position is also important. For example, 2 additional alkyl substitutions at β position will significantly decrease SN2 reaction, potentially making SN1 a better pathway through C+ rearrangement to produce a 3° C+. If β position has neopentyl-like group (3 alkyl substitutions), SN1 will be the only possibility through C+ rearrangement.

Table 3. Factors that impact SN2 and SN1 reaction rates Factors Concentration of substrate Concentration of nucleophile Strength of leaving group Strength of nucleophile Temperature Structure of substrate Solvent

Impact on SN2 rate Concentration doubles, rate doubles Concentration doubles, rate doubles Better leaving group, faster rate Stronger nucleophile, faster rate Higher temperature, higher rate The more substituents at α and β C, the slower the rate; Aprotic solvent increases rate and protic solvent decreases rate

Impact on SN1 rate Concentration doubles, rate doubles No or minimum impact Better leaving group, faster rate No or minimum impact Higher temperature, higher rate The more substituents at α and β C, the faster the rate; Aprotic solvent decreases rate and protic solvent increases rate

Keep in mind that: 1. The concerted step of nucleophilic attack and loss of leaving group is the rate determining step (RDS) in SN2 reaction; the loss of leaving group is the rate determining step in S N1 reaction. 2. Reactants involved in those RDS in SN2 and SN1 dictates the rate law and how the concentration, strength of leaving group and nucleophile impact the reaction rate for both SN2 and SN1 reactions. 3. Activation energy is key in kinetics and SN2 and SN1 competition is indeed highly depend on activation energy. The impact of SN2 and SN1 reaction rates by temperatures, structure of substrate and solvent can all be explained through how they impact the activation energy of SN2 and SN1 reactions....