Chem 341 • Organic Chemistry I Lecture Summary 30 • November 05, 2007

Chapter 11 - Reactions of Alkyl Halides: Nucleophilic Substitutions and Eliminations

SN1 and SN2 Mechanisms

The SN2 mechanism (substitution, nucleophilic, bimolecular) involves the direct substitution of a good leaving group for a nucleophile in a single step. The reaction proceeds through a transition state where there is some bond forming to the nucleophile at the same time the leaving group bond is breaking. The nucleophile must come form the back side of the direction the leaving group is departing resulting in an inversion of the stereocyemstry. The rate of the reaction depends on both the alkyl halide as well as the nucleophile. ‡ R R R

OH + C I HO C I HO C + I R R R RR R

transition state

‡ R HO C I RR SN2 transition A one step reaction state ‡ E - rate = k [R3C-I] [ OH]

reaction progress

The SN1 mechanism (substitution, nucleophilic, unimolecular) occurs in a stepwise fashion where the alkyl halide undergoes loss of the leaving group to form an intermediate carbocation. Note that the nucleophile is not involved at all in the first step, which is the rate determining step. Thus, the rate of the reaction depends only on the substrate concentration. Since a planar carbocation is formed, any stereochemistry information is lost and racemic products are formed.

R R R R RDS OH + C I C + I HO C C OH R R R R RR R R carbocation intermediate

reaction progress

SN2 Reaction Details - Substrate

Since the nucleophile in a SN2 reaction must attack the carbon from the back side (opposite the leaving group) and is involved in the rate determining transition state, the amount of steric bulkiness will have an influence on how well the reaction will proceed. The more substituted the alkyl halide, the harder it is for the nucleophile to approach. Thus, methyl halides are the fastest to react and tertiary halides would be nearly impossible to react.

H R R R

C I C I C I C I SUBSTRATE H H R R H methyl H 1° H 2° R 3°

RELATIVE RATE 2,000,000 40,000 500 <1 FOR SN2

©2007 Gregory R. Cook page 2 Chem 341 North Dakota State University SN2 Reaction Details - Nucleophile The nucleophilicity of a reactant has a very loose correlation with it’s basicity, but they are not - strictly correlated. For example, if you compare H2O with HO , the latter will be more basic AND a more reactive nucleophile. However, If you compare HO- and HS-, the sulfide will be a much much better nucleophile than the hydroxide. However, it is a weaker base. Thus, there is more to nucleophilicity than meets the eye. This has to do with how easily polarized the valence electrons are. If the atom is bigger and the valence electrons are further away from the nucleus, they are more easily polarized when approaching an electrophilic carbon. Thus, they can more easily form a bond. Electronegativity has a better correlation with nucleophilicity than does basicity. The more electronegative the atom, the less polarizable it is.

------NUCLEOPHILE H2O NH3 Cl HO CH3O I CN HS

RELATIVE RATE 1 700 1000 16,000 25,000 100,000 125,000 125,000 FOR SN2

SN2 Reaction Details - Leaving Group The leaving group has a big influence on the substitution reaction as well. The weaker the bond (longer bonds are weaker), the better a leaving group is. Also, the more stable the leaving group is after the bond has broken, the easier it can come off. Thus, more stable anions will be better leaving groups. The tosylate group (-OTos) is one of the best leaving groups.

------LEAVING GROUP TosO I Br Cl F HO NH2

RELATIVE RATE 60,000 30,000 10,000 200 1 <1 <1 FOR SN2

O S O = TosO- Tosylate (p-toluenesulfonate) O

SN2 Reaction Details - Solvents Solvents play a role in dissolving the reactants, stabilizing intermediates and can have positive or negative effects on a reaction. We will discuss the details next time. Here are some examples of common solvents. Note that ‘protic’ solvents can hydrogen bond with lone pairs.

non-polar polar protic polar aprotic solvents solvents solvents O HMPA - alkanes CH C N P CH3 OH 3 hexamethylphosphortriamide (CH3)2N N(CH3)2 acetonitrile N(CH3)2 CH CH OH 3 2 O O H2O S DMSO - C CH CH CH 3 DMF - 3 3 dimethylsulfoxide H N dimethylformamide CH3

SOLVENT CH3OH H2O DMSO DMF CH3CN HMPA

RELATIVE RATE 1 7 1300 2800 5000 200,000 FOR SN2

©2007 Gregory R. Cook page 3 Chem 341 North Dakota State University SN2 Reaction Details - Solvents Solvents play a role in dissolving the reactants, stabilizing intermediates and can have positive or negative effects on a reaction. In the SN2 reaction, the nucleophile strength is important. While solvents that are polar help any substitution reaction, protic solvents will retard the rate of SN2 reactions. This is because the acidic nature of the protons on water or alcohols will surround the nucleophile to stabilize it and render it less reactive. Polar aprotic solvents are best for SN2. δ- O CH δ+ CH 3 3 H3C S S δ+ CH H3C δ- O CH3 3 - δ- δ+S δ S δ+ O O Polar aprotic solvents can CH3 CH3 δ- Na δ- Nuc separate and stabilize ionic O O reagents. - H3C S δ O S CH3 δ+ δ+ δ+ CH3 CH3 S CH3 CH3 S CH3 δ+ CH3 O δ-

H O H O O H H H H Polar protic solvents like water will surround a H nucleophile making it less reactive. Thus, protic Nuc H O H O solvents retard the rate of SN2 reactions. H H H H O O H

SN1 Reaction Details - Substrate

Since the nucleophile is not involved in the rate determining step of the SN1 reaction, the important feature here is the stability of the carbocation intermediate that is being formed. Tertiary substrates are best for this reaction. Secondary substrates are very slow, however if they are next to an alkene, resonance can greatly stabilize the carbocation and make SN1 more favorable. H R R R

C I C I C I C I SUBSTRATE H H R R H methyl H 1° H 2° R 3°

RELATIVE RATE 1 1 12 1,200,000 FOR SN1

The nucleophile is not very important for a SN1 reaction. This is because it is not involved in the rate determining step. Even weak nucleophiles like neutral water will react with a carbocation when it’s formed. The major concern is problems with competing elimination reactions when the nucleophile is too basic.

SN1 Reaction Details - Leaving Group

The leaving group has a big influence on the substitution reaction for SN1 just as we saw with SN2 since the leaving group leaves in the rate determining step. The weaker the bond (longer bonds are weaker), the better a leaving group is. Also, the more stable the leaving group is after the bond has broken, the easier it can come off. Thus, more stable anions will be better leaving groups. The tosylate group (-OTos) is one of the best leaving groups.

SN1 Reaction Details - Solvents

What was bad for the nucleophile in SN2 reactions is great for the leaving group as it comes off. The protic solvents will stabilize the anion with it’s acidic protons. Also, the polar solvents will stabilized the carbocation when it’s formed. Thus, polar protic solvents are best for aiding the rate determining step of the SN1 reaction. H H H H O δ− O H H O O H δ− Polar solvents O H Protic solvents δ− H stabilize the H H H stabilize the leaving O R O carbocation by group by δ− surrounding it with H surrounding it with H H H the negatively O H Br O acidic protons δ− δ− charged oxygens H O O H H H H H H H O O H Stereochemistry of Substitution Reactions

SN2 reactions on chiral substrates will proceed with complete inversion of the stereochemistry. In a SN1 reaction, stereochemistry is lost when you form the planar (achiral) carbocation. The nucleophile may approach from either side with equal probability. Thus, racemic products are formed. Br CN NaCN DMSO

SN2

Br OAc OAc NaOAc Acetic Acid + SN1

50 : 50

©2007 Gregory R. Cook page 5 Chem 341 North Dakota State University SN1 and SN2 Comparison Below is a table comparing the features important for each mechanism for substitution. The substrate type is probably the most important factor.

SN1 SN2

SUBSTRATE 3° >> 2° > 1° 1° > 2° >> 3°

NUCLEOPHILE Weak OK Strong

LEAVING GROUP Stable Anions Stable Anions

SOLVENT Polar Protic Polar Aprotic

STEREOCHEM Racemic 100% inversion

Here are some examples of the affects of these mechanisms on the reaction of an alcohol. Note that carbocations generated during SN1 reactions can undergo rearrangements. An alcohol can be activated into a leaving group two ways . . making a tosylate or making a halide. Note that the tosylate formation does not alter the C-O bond stereochemistry whereas PBr3 or SOCl2 will invert the alcohol stereochemistry when the halide is formed. Nucleophiles and halides in the same molecule can undergo cyclization reactions. carbocation OH rearrangement HBr Br

OH O Tos CN Tos-Cl NaCN

pyridine DMF inversion OH Br CN PBr3 NaCN DMF inversion inversion

Br Br O NaH OH O