Alkyl Halides and Nucleophilic Subs5tu5on Reac5ons S N 2 and S N 1 Reac,ons 1
Alkyl Halides The electronega5ve halogen atom in alkyl halides creates a polar C X bond, making the carbon atom electron deficient. Electrosta5c poten5al maps of four halomethanes (CH 3 X) 2
Reac5ons of Alkyl Halides 3
Nucleophilic Subs5tu5on Reac5ons H 3 C Cl NaOH H 3 C H + NaCl H H Acetone H OH cis-1-chloro-3-methylcyclopentane trans-3-methylcyclohexanol Br NaOH OH + NaBr Acetone R-2-Bromooctane S-2-Octanol OH H 2 O + + HBr Br OH 2-Bromo-3-methylbutane 2-Methyl-2-butanol 3-Methyl-2-butanol 4
Possible Mechanisms of Nucleophilic Subs5tu5on Reac5ons R-X + Nuclophile R-Nucleophile + X 1 st Possibility: Nucleophile R X R-Nucleophile + X 2 nd Possibility: R X Slow step R + X Nuclophile R-Nucleophile 5
Nucleophilic Subs5tu5on Reac5on CH 3 Br OH CH 3 OH + Br 6
Subs5tu5on Nucleophilic Bimolecular, a.k.a. S N 2 Reac5on Rate = k [Alkyl halide]*[nucleophile] The rate of an S N 2 reac<on depends upon 4 factors: 1. The nature of the substrate (the alkyl halide) 2. The power of the nucleophile 3. The ability of the leaving group to leave 4. The nature of the solvent 7
Rela5ve Rates of S N 2 Reac5on for Several Alkyl Bromides 8
Effect of Nature of Substrate on Rate of S N 2 Reac5ons methyl bromide ethyl bromide isopropyl bromide t- butyl bromide SPACE FILLING MODELS SHOW ACTUAL SHAPES AND RELATIVE SIZES Back side of α- C of a methyl halide is unhindered. Back side of α- C of a 1 alkyl halide is slightly hindered. Me >> 1 >> 2 >> 3 Back side of α- C of a 2 alkyl halide is mostly hindered. Back side of α- C of a 3 alkyl halide is completely blocked. decreasing rate of S N 2 reac)ons 9
Effect of the Nucleophile on Rate of S N 2 Reac5ons The α- carbon in vinyl and aryl halides, as in 3 carboca<ons, is completely hindered and these alkyl halides do not undergo S N 2 reac<ons. vinyl bromide bromobenzene Nu: - Nu: - The overlapping p- orbitals that form the π- bonds in vinyl and aryl halides completely block the access of a nucleophile to the back side of the α- carbon. 10
Possible Mechanism and Energy Diagram for S N 2 Reac5on CH 3 Br OH CH 3 OH + Br H e n e r g y CH 3 Br HO H H Br = ΔG CH 3 OH ΔG o Increasing the number of R groups on the carbon with the leaving group increases crowding in the transi5on state, thereby decreasing the reac5on rate. The S N 2 reac5on is fastest with unhindered halides. reaction progress 11
Nucleophiles in S N 2 Reac5on 12
The Nucleophile Bases are beeer nucleophiles than their conjugate acids. Ex: OH - versus H 2 O In going from leh to right across a period basicity and nucleophilicity decreases. Ex: NH 3 versus H 2 O In going down a group in the periodic table, nucleophilicity increases and basicity decreases. Ex: I - versus Cl - For two nucleophiles with the same nucleophilic atom, the stronger base is the stronger nucleophile. Ex: CH 3 O - versus CH 3 CO 2 - Nucleophilicity does not parallel basicity when steric hindrance becomes important. Steric hindrance decreases nucleophilicity but not basicity. 13
Rela5ve Rates of S N 2 Reac5ons for Several Living Groups Cl CH 3 -LG CH 3 Cl + LG A good leaving group reduces the barrier to a reac5on. Stable anions that are weak bases are usually excellent leaving groups and can delocalize charge. O S O O 14
Rela5ve Rates of S N 2 Reac5ons in Several Solvents N N P O N O N S O Hexamethylphosphoramide (HMPA) N,N-Dimethylformamide (DMF) Dimethyl sulfoxide (DMSO) 15
S N 2 Reac5on and Solvent Polar apro5c solvents solvate ca5ons by ion dipole interac5ons. Anions are not well solvated because the solvent. These anions are said to be naked. 16
Examples of S N 2 Reac5on H 3 C H Cl H NaOH Acetone H 3 C H H OH + NaCl cis-1-chloro-3-methylcyclopentane trans-3-methylcyclohexanol Br NaOH OH + NaBr R-2-Bromooctane Acetone S-2-Octanol 17
Subs5tu5on Nucleophilic Unimolecular: S N 1 Reac5ons Slow step R LG R + LG Nuclophile R-Nucleophile Rate = k [R- LG] The Rate of S N 1 Reac5on depends upon 3 factors: 1. The nature of the substrate (alkyl halide) 2. The ability of the leaving group to leave 3. The type of solvent 18
S N 1 Reac5on and The Substrate 19
S N 1 Energy Diagram and Mechanism Rate- determining step is forma5on of carboca5on rate = k[rx] 20
Stereochemistry of S N 1 Reaction The planar intermediate leads to loss of chirality A free carboca5on is achiral Product is racemic or has some inversion 21
S N 1 Reac5on Stereochemistry If leaving group remains associated, then product has more inversion than reten5on. Product is only par5ally racemic with more inversion than reten5on. Associated carboca5on and leaving group is an ion pair. 22
S N 1 in Reality Carboca5on is biased to react on side opposite leaving group Suggests reac5on occurs with carboca5on loosely associated with leaving group during nucleophilic addi5on (Ion Pair) Alterna5ve that S N 2 is also occurring is unlikely 23
Characteristics of the S N 1 Reaction Substrate Ter5ary alkyl halide is most reac5ve by this mechanism Controlled by stability of carboca5on Remember Hammond postulate, Any factor that stabilizes a high- energy intermediate stabilizes transi5on state leading to that intermediate Allylic and benzylic intermediates stabilized by delocaliza5on of charge Primary allylic and benzylic are also more reac5ve in the S N 2 mechanism 24
Nucleophiles in S N 1 Since nucleophilic addi5on occurs a-er forma5on of carboca5on, reac5on rate is not normally affected by nature or concentra5on of nucleophile 25
Rela5ve Rates of S N 1 Reac5ons in Different Solvents 26
Effect of Leaving Group on S N 1 Cri5cally dependent on leaving group Reac5vity: the larger halides ions are beeer leaving groups In acid, OH of an alcohol is protonated and leaving group is H 2 O, which is s5ll less reac5ve than halide p- Toluensulfonate (TosO - ) is excellent leaving group 27
Solvent in S N 1 Stabilizing carboca5on also stabilizes associated transi5on state and controls rate Pro5c solvents favoring the S N 1 reac5on are due largely to stabiliza5on of the transi5on state Pro5c solvents disfavor the S N 2 reac5on by stabilizing the ground state Polar, pro5c and unreac5ve Lewis base solvents facilitate forma5on of R + 28
Examples of S N 1 Reac5ons OH H 2 O + + HBr Br OH 2-Bromo-3-methylbutane 2-Methyl-2-butanol 3-Methyl-2-butanol 29
Predic5ng the Likely Mechanism of a Subs5tu5on Reac5on Four factors are relevant in predic5ng whether a given reac5on is likely to proceed by an S N 1 or an S N 2 reac5on The most important is the iden5ty of the alkyl halide 30
Predic5ng the Likely Mechanism of a Subs5tu5on Reac5on The nature of the nucleophile is another factor. Strong nucleophiles (which usually bear a nega5ve charge) present in high concentra5ons favor S N 2 reac5ons. Weak nucleophiles, such as H 2 O and ROH favor S N 1 reac5ons by decreasing the rate of any compe5ng S N 2 reac5on. Very Good Nucleophiles Good Nucleophiles Fair Nucleophiles Weak Nucleophiles Very Weak Nucleophiles I -, HS -, RS - Br -, OH -, RO -, CN -, N - 3 NH 3, Cl -, F -, RCO - 2 H 2 O, ROH RCO 2 H 31
Predic5ng the Likely Mechanism of a Subs5tu5on Reac5on A beeer leaving group increases the rate of both S N 1 and S N 2 reac5ons. The nature of the solvent is a fourth factor. Polar pro5c solvents like H 2 O and ROH favor S N 1 reac5ons because the ionic intermediates (both ca5ons and anions) are stabilized by solva5on. Polar apro5c solvents favor S N 2 reac5ons because nucleophiles are not well solvated, and therefore, are more nucleophilic. 32
Summary of S N 1 and S N 2 Reac5ons 33