Organic Chemistry Chapter 8

Substitution and Elimination If an sp 3 C is bonded to electronegative atom Substitution reactions and Elimination reactions are possible This chapter is all about substitution

S N 2 and S N 1 Reactions SN2 - Reaction – bonds break and form at the same time example SN1 - CX bond breaks, forming a C+ then reacts with a nucleophile SN1SN1 SN2SN2

Nucleophilic Substitution Reactions Either mechanism depends on the: structure of the alkyl halide reactivity of the nucleophile concentration of the nucleophile The solvent in which the Rx is carried out The leaving group

S N 2 Mechanism It’s a Substitution Reaction (S) It’s Nucleophilic (N) It’s rate is second order (2) –Called bimolecular (rate is dependent on 2 reactants) (Substitution Nucleophilic Bimolecular) Rate = k [RX] [Nu:] (Because rate is dependent of BOTH RX and Nu: it is 2 nd. order.)

S N 2 Mechanism S N 2 Mechanism involves a “backside attack”

S N 2 Mechanism The “backside attack” causes an Inversion of Configuration Careful now….. Doesn’t mean R becomes S – new atoms are involved

Steric Hindrance Groups that block the path from the nucleophile to the electrophilic atom produce steric hindrance This results in a rate differences or no reaction at all methyl halide ethyl halide isopropyl halide t-butyl halide

Steric Hindrance Activation Energy is higher due to steric hindrance…..

Substitution Reactions Depend on a Good Leaving Group R-Falkyl fluorides R-Clalkyl chlorides R-Bralkyl bromides R-Ialkyl iodides Alkyl Halides make good “leaving groups” –They are easily displaced by another atom –They allow the Conversion of alkyl halides to other functional groups

S N 2 Mechanism The Leaving Groups also affects rate RI reacts fastest, RF slowest –Iodide is the best “leaving group” –Fluoride is the worst “leaving group” (…reacting with the same alkyl halide under the same conditions)

Basicity The weaker the basicity of a group, the better the leaving ability. (Lewis base = e - pair donor) –Leaving ability depends on basicity because a weak base does not SHARE its e - as well as a strong base. –Weak bases are not strongly bonded to a carbon (weak bases are GOOD leaving groups)

Nucleophiles – Strong/Weak Good/Bad Stronger base Weaker base Better nucleophile poorer nucleophile OH - >H 2 O CH 3 O - >CH 3 OH - NH 2 >NH 3 CH 3 CH 2 NH - >CH 3 CH 2 NH 2 (conjugate acids)

Nucleophiles The strength of nucleophile depends on reaction conditions. In the GAS phase (not usually used), direct relationship between basicity and nucleophilicity

Solvent Effects In a solution phase reaction, the solvent plays a large role in how the reaction will occur Solvent effects can cause just the opposite of what might be the expected behavior of the nucleophile Solvents are categorized as either protic or aprotic

Protic Solvents Protic solvents has a H bonded to a N or O –It is a H bonder –Examples: H 2 O, CH 3 OH, NH 3, etc –Solvent is attracted to the Nucleophile and hinders its ability to attack the electrophile

Aprotic Solvents Use an aprotic solvent Solvates cations Does not H bond with anions (nucleophile free) Partial + charge is on inside of molecule Negative charge on surface of molecule (solvates cation) Examples include: –DMSO (dimethyl sulfoxide) –DMF (dimethyl formamide) –Acetone (CH 3 COCH 3 ) DMSO DMF

Nucleophiles In the organic solvent phase, INVERSE relationship between basicity and nucleophilicity with a protic solvent Question…

Nucleophiles Solvents can solvate the nucleophile –Usually this is NOT good because the nucleophile is “tied up” in the solvent and LESS REACTIVE. Ion-dipole interactions

Nucleophiles Solvents can solvate the nucleophile (Methanol is a polar protic solvent.)

S N 2 Reactions

S N 2 reactions might be reversible Leaving group would become the nucleophile Compare basicity (nucleophile strength) to see which is a better leaving group. The stronger base will displace the weaker base –If basicity is similar, the Rx will be reversible

S N 2 Reactions Compare basicity to see which is a better nucleophile.

S N 1 Reactions Reaction of t-butyl bromide with water should be slow –water is a poor nucleophile –t-butyl bromide is sterically hindered However –Reaction is a million times faster than with CH 3 Br (Maybe not an S N 2 reaction!)

S N 1 Reactions

S N 1 Mechanism Rate determining step does not involve nucleophile Step 2 Step 1

S N 1 Mechanism

S N 1 Reactivity Relative Reactivities in an S N 1 Reaction 1 o RX < 2 o RX < 3 o RX Increasing Reactivity

S N 1 Stereochemistry Because a planer carbocation is formed, nucleophilic attack is possible on both sides, so both isomers are possible

S N 1 Stereochemistry SN1 should yield racemic mixture but it doesn’t This is due to the steric hindrance of the leaving group

Stereochemistry As the leaving group goes (Marvin K) it blocks the path of any incoming nucleophiles

S N 1 vs S N 2 Inversion of configuration racemization with partial inversion

What Makes S N 1 Reactions work the best Good Leaving Group –The weaker the base, the less tightly it is held (I - and Br - are weak bases) Carbocation –How stable is the resulting carbocation? 3 o > 2 o > 1 o > methyl Increasing Stability

What Doesn’t Matter In an S N 1 Reactions The Nucleophile It has NO EFFECT on rate of Rx!!! Solvolysis Reactions (the nucleophile is also the solvent)

Carbocation Rearrangements Since a carbocation is the intermediate, you may see rearrangements in an S N 1 Rx No rearrangements in an SN2 Rx

Carbocation Rearrangement Methyl Shift

Benzylic, Allylic, Vinylic, and Aryl Halides Benzylic and allylic halides can readily undergo S N 2 unless they are 3 o –(steric hindrance)

Benzylic, Allylic, Vinylic, and Aryl Halides B enzylic and allylic halides can also undergo S N 1 (they form stable carbocations) Even though 1 o RX do not go S N 1, 1 o benzylic and 1 o allylic CAN react S N 1!

Vinylic,and Aryl Halides Vinylic halides and aryl halides –do not undergo S N 1 or SN 2 reactions!  e - repel incoming Nucleophile

S N 1 vs S N 2 Review

S N 1 vs S N 2 Methyl, 1 o RX … 2 o RX … 3 o RX … Vinylic, aryl RX … 1 o, 2 o benzylic, allylic RX … 3 o benzylic, allylic RX … S N 2 only S N 1 and S N 2 S N 1 only neither S N 1 nor S N 2 S N 1 and S N 2 S N 1 only

Role of the Solvent In an S N 1, a carbocation and halide ion are formed –Solvation provides the energy for X - being formed –In S N 1 the solvent “pulls apart” the alkyl halide –S N 1 cannot take place in a nonpolar solvent or in the gas phase –Increasing the polarity of the solvent will INCREASE the rate of Rx if none of the REACTANTS are charged. –If reactants are charged it will DECREASE the rate.

Role of the Solvent So…. In an S N 1 reaction, the reactant is RX. The intermediate is charged and is STABILIZED by a POLAR solvent A POLAR solvent increases the rate of reaction for an S N 1 reaction. (However, this is true only if the reactant is uncharged.)

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Role of the Solvent In S N 2 In an S N 2 reaction, one of the reactants is the nucleophile (usually charged). The POLAR solvent will usually stabilize the nucleophile. A POLAR solvent decreases the rate of reaction for an S N 2 reaction. (However, this is true only if the nucleophile is charged.)

Polar Aprotic Solvents Polar Aprotic Solvents include: –DMFN,N-dimethylformamide –DMSOdimethylsulfoxide –HMPAhexamethylphosphoramide –THFTetrahydrofuran –And even… acetone

Polar Aprotic Solvents –do not H bond –solvate cations well –do NOT solvate anions (nucleophiles) well –good solvents for S N 2 reactions

Polar Aprotic Solvents DMSO DMF Acetone HMPA

Nucleophile Review

S N 1/S N 2 Problems -1 Predict the type of mechanism for this reaction, and the stereochemistry of each product

S N 1/S N 2 Problems -1 Predict the type of mechanism for this reaction, and the stereochemistry of each product

S N 1/S N 2 Problems -2 Predict the mechanism of this reaction

S N 1/S N 2 Problems -2 Predict the mechanism of this reaction

S N 1/S N 2 Problems -3 Predict the mechanism. If the starting material has the R configuration, predict the configuration of product

S N 1/S N 2 Problems -3 Predict the mechanism. If the starting material has the R configuration, predict the configuration of product

S N 1/S N 2 Problems -4 Predict the mechanism + acetic acid Br OCCH 3 O O CH 3 COH + HBr

S N 1/S N 2 Problems -4 Predict the mechanism + acetic acid Br OCCH 3 O O CH 3 COH + HBr

S N 1/S N 2 Problems -5 Predict the mechanism

S N 1/S N 2 Problems -5 Predict the mechanism

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