Nucleophilic Substitution overview Mechanism of SN rxn: SN1 (stepwise) vs. SN2 (concerted): Kinetics; Stereochemistry outcome; Changes involved in SN rxn: Proton transfer; Carbocation rearrangement; Solvolysis Factors affecting SN1 vs. SN2: substrate; Nuc; LG; solvent

Chapter Objectives Predict the reaction pathway and draw reaction mechanism Predict the main products Design synthetic pathway based on chapter learning (choice of substrate, nucleophile, leaving group, and solvent)

Substitution Rxn One group of atoms is replaced with another Generic example A + B-C  A-B + C Specific example It involves a nucleophile and an electrophile Very common organic chemical rxn.

Substitution reactions During the substitution, one group ATTACKS (forming bond) and one group LEAVES (breaking bond): A leaving group always takes a pair of electrons with it. Find leaving group in the follows:

Substitution reactions Substitution rxn equilibrium depends on the relative strength of base (nucleophile) involved. Strong base (Nuc:) will react to yield weak base (as leaving group, LG)

Leaving Group (LG) What makes a good leaving group: The electronegative leaving group creates a partial charge on the site of attack to attract the negative charge of the nucleophile The Leaving Group must be able to stabilize the electrons it leaves with (conjugate base from stronger acid. ARIO)

Find Good LG? Candidates as good leaving groups according to the two key criteria? Create a positive charge to attract the nucleophile. High electronegativity (EN > 2.1: N, O, F; P, S, Cl; Se, Br; I) 2. Be able to stabilize the electrons it leaves with, conjugate base of strong acid What are the strong acids? ARIO: HX (X = Cl, Br, I), oxyacids, carboxylic acids

Substrate I: Alkyl Halides Alkyl halides are compounds where a carbon group (alkyl) is bonded to a halide (F, Cl, Br, or I) Alkyl halides are important compound in substitution rxn, attacked by nucleophile. Known as substrate Self study: refer to the end of this file for more nomenclature info. Recall from Nomenclature of Alkane Identify and name the parent chain Identify the name of the substituents Assign a locant (number) to each substituents Assemble the name alphabetically

Alkyl Halide Structure: a-, b-, g- Greek letters to label the carbons of the alkyl group attached to the halide Substitutions occur at the a-carbon Classification of alkyl halides (here R = alkyl) based on #alkyl groups on a-carbon

Practice: Alkyl Halides 1, 2, 3 Lindane wased as insecticides. For the circled atoms, label all of the alpha, beta, gamma, and delta carbons.

Review: Four arrow pushings Bond forming vs. Bond breaking

Substitution Mechanisms EVERY nucleophilic substitution reaction will involve nucleophilic attack and loss of a leaving group The order that these steps occur can vary Possibility of proton transfer or rearrangement

SN2: a concerted mechanism Kinetics: If the concerted rxn above is the only step in the mechanism, the rate law for this reaction will be: rate = k[Nu:-][C-LG] This mechanism shows a second order rate law for nucleophilic substitution, thus SN2

Stereochemistry of SN2 SN2 mechanism: simultaneous bond forming (attacking Nu:- and C-LG) and bond breaking of C-LG) Being a tetrahedral carbon, with all the remaining C-Y bonds in the same order, the C-Nu is in the opposite side compared to C-LG (Inversion). Experiments showed the agreement between kinetics and stereochemistry.

Transition state for SN2 Extended dotted lines to represent bonds breaking and forming Transition state symbol

SN2: Potential Energy Diagram Thermodynamically controlled reaction: high activation energy and exergonic rxn.

Steric Effect on SN2 kinetics Less stericly hindered electrophiles react more readily under SN2 conditions

Steric Effect on SN2: Ea 3° substrates react too slow. Significant side reaction

Practice: SN2 rxn for alkyl halide? SN reaction for neopentyl bromide Is neopentyl bromide a primary, secondary, or tertiary alkyl bromide? Predict if neopentyl bromide react by an SN2 reaction relatively quickly or relatively slowly Exception to the common pattern! It is better to understand the concepts than to memorize rules

SN1 : a step-wise mechanism The reaction begins with a unimolecular decomposition process. Thus SN1 Kinetic experiments would predict the rate law as:

SN1 reaction coordinate The two-step mechanism: Two transitions states (heterolytic bond breaking; nucleophilic attack forming bond) Carbocation as intermediate Nucleophile may attack from both sides

SN1: First step determines the rate law First step involves large Ea, therefore is slow. Thus the rate depends only on [electrophile] and NOT [nucleophile].

Kinetics: SN1 vs. SN2 Consider the following generic SN2 reaction: [Nuc:-] affects the rate of SN2 reaction. Consider the following generic SN1 reaction: [Nuc:-] does NOT affect the rate of SN1 rxn

Structure of Substrate in SN1 rxn The structure-rate relationship for SN1 is the opposite of what it was for SN2. The relative stability of carbocation (hyperconjugation) affects the Transition state (Ea).

Carbocation as Intermediate in SN1 mechanism A carbocation forms during the mechanism. Hyperconjugation: Carbocation with more alkyl substitutents should be more stable.

Relative stability of Carbocation Hyperconjugation: C-H orbital semiparallel with the empty p orbital in carbocation

More stable Intermediate, Lower Ea Hammond postulate: proximal in reaction coordinate, similar energy and similar structure. Primary substrates react too slowly to measure.

Stereochemistry of SN1 Recall the SN2 product is inversed from reactant. Carbocation has sp2 hybridization, allowing Nu:- to attack from both sides, forming both R and S product (50% and 50%).

*Ion pair causes inversion in SN1 The formation of ion pairs can cause inversion to occur slightly more often than retention

SN2 vs. SN1: Summary

Protonation promotes SN1 of alcohol SN1 demands good LG (weak base HOSO3-, I-, H2O, derived from strong acid, H2SO4, HI, H3O+, etc) OH as poor leaving group Protonation of C-OH gives C-+OH2 (H2O as good LG)

SN1 with Protonation in Mechanisms 1. Protonation; 2. Forming carbocation; 3. Nu:- attack

SN1 with Deprotonation In SN1, proton transfer steps often occur after the substitution by weak nucleophile. Write mechanism:

Carbocation rearrangement in SN1 Carbocation in SN1 reactions may rearrange to form more stable carbocation. When carbocation is next to quartanery (4) carbon atom, rearrangement is likely. Predict the final product(s).

Mechanism: SN1 vs. SN2 Summary of considerations to make Will proton transfers be necessary? look at the quality of the leaving group Look at the stability of the final product Will the mechanism be SN1 or SN2? look at how crowded the electrophilic site is Look at how stable the resulting carbocation would be Are rearrangements likely? look for ways to improve the stability of the carbocation Will the product have inversion or racemization? SN1=racemization while SN2=inversion

Protonation in SN2 Mechanisms Proton transfer often takes place when acid is present in the SN2 reactions.

Protonation & Deprotonation Proton transfer steps occur often in SN2 reactions, similar to SN1 reactions.

Protonation gives better LG in SN2 Protonation of three-membered ring (high energy) greatly facilitates the hydrolysis, as protonated ROH is weaker base than RO-. Qualitatively, this reaction has negative H and negative S.

More SN2 Mechanisms Another example: only Deprotonation is involved. carbocation rearrangements not possible in SN2 If rearrangement is observed, SN1 pathway more likely

SN1 vs. SN2: Which pathway to follow? Four main factors to determine whether a substitution reaction is more likely to occur by SN1 or SN2 (in the order of importance from high to low): The substrate (both STERIC effect and the stability of the CARBOCATION): sterically hindered or stable carbocation favors SN1 pathway. The quality of the leaving group The strength of the nucleophile The solvent

Unsaturated groups in OChem Vinyl Allyl Benzyl Aryl

Carbocation Stability The stability of the resulting carbocation If a relatively stable carbocation can form when the LG leaves, the mechanism may be SN1 Stability of carbocations: ARIO INDUCTION – electron-pulling destabilizes RESONANCE – allylic and benzylic,  carbon is sp2

Resonance in Carbocation Recall: Resonance stabilizes both allylic and benzylic carbocations Thus allylic and benzylic halides more likely to undergo SN1

SN1 for Vinyl or Aryl Halides? Consider carbocation stability from vinyl and aryl halides via SN1 pathway: Poor stability of such carbocations due to lack of resonance: vacant sp2 orbital, not p orbital. Thus no SN1 pathway.

SN1 vs. SN2: Leaving Group Good Stability of LG- Makes good LG The conjugate base of a strong acid: stable anion once dissociated WITH a pair of electrons. Conjugate base of a weak acid is bad LG. Solvation Examples of good LG: C2H3O2-, NO3-, RSO3-, H2O, etc. Examples of bad LG: H-, OH-, CH3O-, NH2-, CH3- Unstable LG is unfavorable for either SN1 or SN2.

Common Leaving Groups Halide ions and sulfonate ions (from strong acids) Sulfonate ion as LG are commonly used in organic synthesis. Tosylate often as OTs Demo: Bromide > Chloride Memorize the good LG!

Nucleophilicity Strength of nucleophile: rate of SN2 reaction Very Good I-, HS-, RS- Good Br-, HO-, RO-, CN-, N3- Fair NH3, Cl-, F-, RCO2- Weak H2O, ROH Very Weak RCO2H Strength of nucleophile: rate of SN2 reaction Stability (induction, resonance, polarizibility, solvation) Sterics Strong nucleophile favor SN2 Weak nucleophile incapable of SN2 but allowed in SN1, as the reaction rate of SN1 is independent of [Nu:-] SN2 requires good nucleophile

Nucleophile in SN1 vs. SN2 A stronger nucleophile favors SN2 , although it may react by SN1 if the substrate is NOT sterically hindered and the leaving group is good. A weaker nucleophile favors SN1, although it may react by SN2 if the substrate can NOT stabilize a carbocation effectively, and the leaving group is poor. Remember these Nu:-!

Solvent affects Transition state The solvent ( ) surrounds each species in the mechanism including the transition state δ+ δ- δ- δ+ δ- δ+

Protic vs. Polar Aprotic solvents Protic solvents are used for SN1. Such as H2O and alcohol, as Both cation and nucleophile anion are stabilized. Polar aprotic solvents are used for SN2. Such as DMSO, CH3CN, DMF, HMPA. Anions (nucleophile) are NOT stabilized.

Solvent affects Halide Nucleophilicity The relative reactivity of halide ion (as Nu:-) depends on solvent: In a polar, protic solvent, F- < Cl- < Br- < I-. Fluoride ion is tightly bound to the solvent shell, least available for nucleophilic substitution. In a polar, aprotic solvent, F- > Cl- > Br- > I-. There is no solvent shell, thus smaller anions are less stable and more reactive.

Designing Syntheses Organic synthesis: Convert available substrates to the target molecule (specific structure and stereochemistry) How do we use what we have learned to set up successful reactions? We must choose appropriate substrate, reaction condition (reagent, temperature, solvent, catalyst, etc.).

Syntheses via SN1 or SN2? 1° substrate adopts SN2 only (inversion product): Good Nu:- (from weak acid) Leaving Group: No preference. Solvent: Polar aprotic (DMSO, DMF, HMPA, MeCN) 3° substrate goes through SN1 (racemic product): Nucleophile Not important Good LG Solvent: Polar protic (water, alcohol, etc.)

In Between: 2° substrate The reaction could be SN1 or SN2, depending on the desired stereochemistry for the product. To achieve inversion product, SN2 pathway is needed. Otherwise, both pathways are available. The choice of the following depends on whether SN1 or SN2 pathway is chosen, like in previous slide. Nucleophile? Leaving Group? Solvent?

Designing Syntheses Some options and choices:

Example: Designing Syntheses Design a synthesis (reagent/Nu:-, solvent, LG) for the following molecule A starting from (R)-2-chlorobutane B. The enantiomer of A.

Example: Designing Syntheses Acidic condition: -OH may be converted to –OH2+ as better LG. Rearrangement might occur due to carbocation Sometimes convert –OH to -OTs as better LG

Alkyl Halide Nomenclature For each of these examples, convince yourself that they are numbered in the most appropriate way.

Alkyl Halide Nomenclature Some simple molecules are also recognized by their common names. the alkyl group is named as the substituent, and the halide is treated as the parent name Methylene chloride is a commonly used organic solvent

Alkyl Halide Nomenclature Give reasonable names for the following molecules

Additional Practice Problems Give reasonable names for the following molecules Label each halide as primary, secondary, or tertiary

Additional Practice Problems Give the best set of reaction conditions to promote SN2 for the following substrate. Describe experiments that could be done to support the proposed mechanism

Additional Practice Problems Give the best set of reaction conditions to promote SN1 for the following substrate. Describe experiments that could be done to support the proposed mechanism

Additional Practice Problems Propose reaction conditions and give a complete mechanism for the following substitution reaction

Additional Practice Problems Give a complete mechanism for the following substitution reaction

SN1 with Protonation in Mechanisms 1. Protonation; 2. Forming carbocation (Dehydration); 3. Nu:- attack

Carbocation rearrangement in SN1 Carbocation in SN1 reactions may rearrange to form more stable carbocation. When carbocation is next to quartanery (4) carbon atom, rearrangement is likely. Predict the final product(s).

Protonation in SN2 Mechanisms Proton transfer often takes place when acid is present in the SN2 reactions.

Protonation & Deprotonation Proton transfer steps occur often in SN2 reactions, similar to SN1 reactions.

Protonation gives better LG in SN2 Protonation of three-membered ring (high energy) greatly facilitates the hydrolysis, as protonated ROH is weaker base than RO-. Qualitatively, this reaction has negative H and negative S.

More SN2 Mechanisms Another example: only Deprotonation is involved. carbocation rearrangements not possible in SN2 If rearrangement is observed, SN1 pathway more likely

Resonance in Carbocation Recall: Resonance stabilizes both allylic and benzylic carbocations Thus allylic and benzylic halides more likely to undergo SN1

SN1 for Vinyl or Aryl Halides? Consider carbocation stability from vinyl and aryl halides via SN1 pathway: Poor stability of such carbocations due to lack of resonance: vacant sp2 orbital, not p orbital. Thus no SN1 pathway.

*MO theory: HOMO vs. LUMO Many rxns involve orbital interaction as HOMO (highest occupied MO) with LUMO (lowest unoccupied MO). HOME is electron pair donor (nucleophile, Lewis base). LUMO is electron pair acceptor (electrophile, Lewis acid) When HOMO and LUMO orbitals are in phase (sharing same sign), bond may form. Nu:- forms bond with HOMO with the LUMO from C-LG

*Molecular Orbital Theory on SN2: Why nucleophile attacks from the back-side Electron density from LG repels the attacking Nu:- from the front-side Nu:- must approach the back-side to allow electrons to flow from HOMO of the nucleophile to LUMO of the electrophile. Proper orbital overlap cannot occur with front-side attack because there is a node on the front-side of the LUMO

*Example: Experiment  Mechanism Consider the following reaction How likely this rxn proceeds via SN1? SN2? Which product is from inversion? Which from retention. What accounts for the 35%/65% product ratio? Is the reaction reacting more by SN1 or SN2?

Practice: Complete SN1 Mechanisms SN1 or SN2? Proton transfer? Rearrangement? Inversion/Racemization? Predict the reagents necessary to complete this substitution. Draw a complete mechanism

*Alkyl Halide in life Insecticides (DDT, etc.) Fire retardant Polymer: Teflon, PVC Anesthetic (chloroethane, trichloromethane/chlorofoam) *Drugs (anticancer, antidepressants, antimicrobial, etc.) *Food additives (Splenda, etc.)