Chapter 11- Reactions of Alkyl Halides: Nucleophilic Substitutions and Eliminations Ashley Piekarski, Ph.D. Alkyl Halides React with Nucleophiles and Bases Alkyl halides are polarized at the carbon- halide bond, making the carbon electrophilic Nucleophiles will replace the halide in C- X bonds of many alkyl halides(reacgon as Lewis base) Nucleophiles that are Brønsted bases produce eliminagon 1
Why do I care, Dr. P? Nucleophilic subsgtugon, base induced eliminagon are among most widely occurring and versagle reacgon types in organic chemistry ReacGons will be examined closely to see: - How they occur - What their characterisgcs are - How they can be used 11.1 The Discovery of Nucleophilic Substitution Reactions In 1896, Walden showed that (- )- malic acid could be converted to (+)- malic acid by a series of chemical steps with achiral reagents This established that op#cal rota#on was directly related to chirality and that it changes with chemical altera#on Reaction of (-)-malic acid with PCl 5 gives (+)- chlorosuccinic acid Further reaction with wet silver oxide gives (+)-malic acid The reaction series starting with (+) malic acid gives (-) acid 2
Reactions of the Walden Inversion What sort of observagons can we make about the reacgons Walden performed? Significance of the Walden Inversion The reacgons alter the array at the chirality center The reacgons involve subsgtugon at that center Therefore, nucleophilic subsgtugon can invert the configuragon at a chirality center 3
11.2 The S N 2 Reaction ReacGon is with inversion at reacgng center Follows second order reacgon kinegcs the rate is linearly dependent on the concentrations of two species Ingold nomenclature to describe characterisgc step: S=substitution N (subscript) = nucleophilic 2 = both nucleophile and substrate in characteristic step (bimolecular) The S N 2 Reaction-Mechanism 4
Kinetics of Nucleophilic Substitution Rate (R) is change in concentragon with Gme Depends on concentragon(s), temperature, inherent nature of reacgon (barrier on energy surface) A rate law describes relagonship between the concentragon of reactants and conversion to products A rate constant (k) is the proporgonality factor between concentragon and rate Example: for S convergng to P R = d[s]/dt = k [S] Reaction Kinetics The study of rates of reacgons is called kine#cs Rates decrease as concentragons decrease but the rate constant does not Rate units: [concentragon]/gme such as mol/(l x s) The rate law is a result of the mechanism The order of a reacgon is sum of the exponents of the concentragons in the rate law the example is second order 5
S N 2 Process The reacgon involves a transigon state in which both reactants are together S N 2 Transition State The transigon state of an S N 2 reacgon has a planar arrangement of the carbon atom and the remaining three groups 6
11.3 Characteristics of the S N 2 Reaction SensiGve to steric effects Why do you think that is? Methyl halides are most reacgve Primary are next most reacgve Secondary might react TerGary are unreacgve by this path No reacgon at C=C (vinyl halides) 13 Reactant and Transition State Energy Levels Affect Rate Higher reactant energy level (red curve) = faster reacgon (smaller ΔG ). Higher transigon state energy level (red curve) = slower reacgon (larger ΔG ). 14 7
Steric Effects on S N 2 Reactions What are the subsgtugons of these substrates? How would you order the reacgvity? Order of Reactivity in S N 2 The more alkyl groups connected to the reacgng carbon, the slower the reacgon 8
The Nucleophile Neutral or negagvely charged Lewis base ReacGon increases coordinagon at nucleophile Neutral nucleophile acquires positive charge Anionic nucleophile becomes neutral List of Nucleophiles What causes difference in Nucleophilicity? depends on substrate, solvent, and reactant concentra#ons 9
Relative Reactivity of Nucleophiles More basic nucleophiles react faster Beher nucleophiles are lower in a column of the periodic table Why do you think that is? Anions are usually more reacgve than neutrals These types of reactions are generally ran under basic conditions The Leaving Group A good leaving group reduces the barrier to a reacgon Stable anions that are weak bases are usually excellent leaving groups and can delocalize charge 10
The Solvent Solvents that can donate hydrogen bonds (- OH or NH) slow S N 2 reacgons by associagng with reactants Energy is required to break interacgons between reactant and solvent Polar aprogc solvents (no NH, OH, SH) form weaker interacgons with substrate and permit faster reacgon Summary S N 2 What are good substrates? What are good nucleophiles? What makes a good leaving group? What is a good solvent? 11
11.4 The S N 1 Reaction TerGary alkyl halides react rapidly in progc solvents by a mechanism that involves departure of the leaving group prior to addigon of the nucleophile Called an S N 1 reacgon occurs in two disgnct steps while S N 2 occurs with both events in same step If nucleophile is present in reasonable concentragon (or it is the solvent), then ionizagon is the slowest step The S N 1 Reaction-Mechanism 12
S N 1 Energy Diagram R = k[rx] What is missing from the rate law? Rate- determining step is formagon of carbocagon Rate-Limiting Step The overall rate of a reacgon is controlled by the rate of the slowest step The rate depends on the concentragon of the species and the rate constant of the step The highest energy transigon state point on the diagram is that for the rate determining step (which is not always the highest barrier) 13
Stereochemistry of S N 1 Reaction The planar intermediate leads to loss of chirality A free carbocation is achiral Product is racemic S N 1 in Reality CarbocaGon is biased to react on side opposite leaving group Suggests reacgon occurs with carbocagon loosely associated with leaving group during nucleophilic addigon AlternaGve that S N 2 is also occurring is unlikely 14
Not completely racemic products 11.5 Characteristics of the S N 1 Reaction Substrate TerGary alkyl halide is most reacgve by this mechanism Controlled by stability of Any factor that stabilizes a high-energy intermediate stabilizes transition state leading to that intermediate 15
Allylic and Benzylic Halides Allylic and benzylic intermediates stabilized by delocalizagon of charge (Draw the resonance structures for the allyl carbocagon and the benzyl carbocagon) Primary allylic and benzylic are also more reactive in the S N 2 mechanism Effect of Leaving Group on S N 1 CriGcally dependent on leaving group Reactivity: the larger halides ions are better leaving groups Under acidic condigons, OH of an alcohol is protonated and leaving group is H 2 O, which is sgll less reacgve than halide p- Toluenesulfonate (TosO - ) is excellent leaving group 16
Nucleophiles in S N 1 Since nucleophilic addigon occurs a9er formagon of carbocagon, reacgon rate is not normally affected by nature or concentragon of nucleophile Solvent in S N 1 How do you think solvent plays a role in S N 1 reacgons? Stabilizing carbocagon also stabilizes associated transigon state and controls rate Solvent effects in the S N 1 reacgon are due largely to stabilizagon or destabilizagon of the transigon state 17
Polar Solvents Promote Ionization Polar, progc and unreacgve Lewis base solvents facilitate formagon of R + Solvent polarity is measured as dielectric polariza7on (P) Nonpolar solvents have low P Polar solvents have high P values Summary S N 1 What are good substrates? What are good nucleophiles? What makes a good leaving group? What is a good solvent? 18
11.7 Elimination Reactions of Alkyl Halides: Zaitsev s Rule EliminaGon is an alternagve pathway to subsgtugon Opposite of addigon Generates an alkene Can compete with subsgtugon and decrease yield, especially for S N 1 processes Zaitsev s Rule for Elimination Reactions In the eliminagon of HX from an alkyl halide, the more highly subsgtuted alkene product predominates 19
Mechanisms of Elimination Reactions Ingold nomenclature: E eliminagon E1: X - leaves first to generate a carbocagon a base abstracts a proton from the carbocation E2: Concerted transfer of a proton to a base and departure of leaving group E1 Mechanism 20
E2 Mechanism 11.8 The E2 Reaction and the Deuterium Isotope Effect What is the rate law for the E2 reacgon? How does the rate of the reacgon change between hydrogen and deuterium? 21
Geometry of Elimination E2 AnGperiplanar allows orbital overlap and minimizes steric interacgons Periplanar- all four reacgng atoms (the hydrogen, the two carbons, and the leaving group) lie in the same plane E2 Stereochemistry Overlap of the developing sp 3 σ orbital in the transigon state requires periplanar geometry, ang arrangement 22
Predicting Product E2 is stereospecific Meso- 1,2- dibromo- 1,2- diphenylethane with base gives cis 1,2- diphenyl RR or SS 1,2- dibromo- 1,2- diphenylethane gives trans 1,2- diphenyl 11.9 The E2 Reaction and Cyclohexane Formation Abstracted proton and leaving group should align trans- diaxial to be ang periplanar (app) in approaching transigon state Equatorial groups are not in proper alignment 23
E2 and cyclohexanes 11.10 The E1and E1cB Reactions Competes with S N 1 and E2 at 3 centers V = k [RX], same as S N 1 24
E1 Mechanism shows no deuterium isotope effect! Comparing E1 and E2 Strong base is needed for E2 but not for E1 E2 is stereospecifc, E1 is not E1 gives Zaitsev orientagon 25
11.12 Summary of Reactivity: S N 1, S N 1, E1,E1cB, E2 Primary alkyl halides: SN2 subsgtugon occurs if a good nucleophile is used, E2 eliminagon occurs if a strong base is used, E1cB eliminagon occurs if the leaving group is two carbons away from a carbonyl group Secondary alkyl halides: SN2 subsgtugon occurs if a weakly basic nucelophile is used in a polar aprogc solvent, E2 eliminagon predominates if a strong base is used, E1cB eliminagon occurs if the leaving group is two carbons away from a carbonyl group. Secondary allylic and benzylic alkyl halides can also undergo SN1 and E1 reacgons if a weakly basic nucleophile is used in a progc solvent Ter7ary alkyl halides: E2 eliminagon occurs when a base is used, but SN1 and E1 occur together under neutral condigons., E1cB eliminagon occurs if the leaving group is two carbons away from a carbonyl group 26