Substitution Reactions Organic Chemistry Second Edition David Klein Chapter 7 Substitution Reactions Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

7.1 Substitution reactions One group of atoms is replaced with another Generic example Specific example Label the nucleophile and electrophile Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

7.1 Substitution reactions Which side do you think will be favored in the dynamic equilibrium? WHY? Draw a reaction coordinate diagram that illustrates your equilibrium prediction Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

7.1 Substitution reactions During the substitution, one group ATTACKS and one group LEAVES. Can you label them in the reaction? A leaving group always takes a pair of electrons with it. In the reaction below, fill in arrows to show the mechanism and label the leaving group. Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

7.1 Substitution reactions To encourage substitution a good leaving group must fulfill two criteria: 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 Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

7.1 Substitution reactions Can you give some examples of groups of atoms that qualify as good leaving groups according to the two key criteria? Create a positive charge to attract the nucleophile. Be able to stabilize the electrons it leaves with Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

7.2 Alkyl Halides Alkyl halides are compounds where a carbon group (alkyl) is bonded to a halide (F, Cl, Br, or I) Recall from section 4.2 the steps we use to name a molecule Identify and name the parent chain Identify the name of the substituents Assign a locant (number) to each substituents Assemble the name alphabetically The halide group is the key substituent we will name and locate Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

7.2 Alkyl Halide Nomenclature For each of these examples, convince yourself that they are numbered in the most appropriate way. Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

7.2 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 Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

7.2 Alkyl Halide Nomenclature Give reasonable names for the following molecules Try more examples with conceptual checkpoint 7.1 Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

7.2 Alkyl Halide Structure Greek letters are often used to label the carbons of the alkyl group attached to the halide Substitutions occur at the alpha carbon WHY? The amount of branching at the alpha carbon affects the reaction mechanism. There are three types of alkyl halides Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

7.2 Alkyl Halide Structure Some alkyl halides are used as insecticides. For the insecticides below… Label each halide as either primary, secondary, or tertiary For the circled atoms, label all of the alpha, beta, gamma, and delta carbons. Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

7.2 Alkyl Halide Structure Halides appear in a wide variety of natural products and synthetic compounds The structure of the molecule determines its function, and functions include… Insecticides (DDT, etc.) Dyes (tyrian purple, etc.) Drugs (anticancer, antidepressants, antimicrobial, etc.) Food additives (Splenda, etc.) Many more Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

7.2 Alkyl Halide Structure HOW does a molecule’s structure affect its function and properties? Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

7.3 Substitution Mechanisms Recall from chapter 6 the FOUR arrow pushing patterns for ionic processes Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

7.3 Substitution Mechanisms Recall from chapter 6 the arrow pushing patterns for ionic processes Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

7.3 Substitution Mechanisms EVERY nucleophilic substitution reaction will involve nucleophilic attack and the loss of a leaving group The order that these steps occur can vary The inclusion of a proton transfer or rearrangement can also vary Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

7.3 Substitution Mechanisms Draw mechanisms for each possibility and critique their likelihood Nucleophilic attack first then loss of leaving group. Loss of leaving group first then nucleophilic attack Both happen simultaneously Practice arrow pushing with SkillBuilder 7.1 Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

7.4 SN2 – a concerted mechanism How might you write a rate law for this reaction? How would you design a laboratory experiment to test this mechanism? Test yourself with conceptual checkpoint 7.6 Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

7.4 SN2 – stereochemistry What do S, N, and 2 stand for in the SN2 name? How might we use stereochemistry to support the SN2 mechanism for the following reaction? Practice drawing SN2 reactions with SkillBuilder 7.2 Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

7.4 SN2 – backside attack The nucleophile attacks from the back-side Electron density repels the attacking nucleophile from the front-side The nucleophile must approach the back-side to allow electrons to flow from the HOMO of the nucleophile to the 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 Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

7.4 SN2 – backside attack Draw the transition state for the following reaction. Use extended dotted lines to represent bonds breaking and forming Practice drawing transition states with SkillBuilder 7.3 Transition state symbol Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

7.4 SN2 kinetics Less sterically hindered electrophiles react more readily under SN2 conditions. To explain this trend, we must examine the reaction coordinate diagram Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

7.4 SN2 – Rationalizing kinetic data How do we use the diagram to make a kinetic argument? How do we use the diagram to make a thermodynamic argument? Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

7.4 SN2 – Rationalizing kinetic data Which reaction will have the fastest rate of reaction? WHY? 3° substrates react too slowly to measure. Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

7.4 SN2 – Rationalizing kinetic data An example to consider: neopentyl bromide Draw the structure of neopentyl bromide Is neopentyl bromide a primary, secondary, or tertiary alkyl bromide? Should neopentyl bromide react by an SN2 reaction relatively quickly or relatively slowly? WHY? Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

7.4 SN2 – Rationalizing kinetic data If you memorize rules, you will probably miss questions about exceptions to rules It is better to understand the concepts than to memorize rules Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

7.5 SN1 – a step-wise mechanism If kinetic experiments were performed to determine the rate law, you would find that… Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

7.5 SN1 – reaction coordinate A two-step mechanism gives a diagram with two transitions states. Where on the diagram is the intermediate? Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

7.5 SN1 – reaction coordinate What is happening to the molecule in each transition state? Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

7.5 SN1 – reaction coordinate Which step is the RDS and WHY? Why does the rate depend only on [electrophile] and NOT [nucleophile]? Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

7.5 SN1 – a step-wise mechanism What do the S, N, and 1 stand for in the SN1 name? Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

7.5 SN1 – SN2 Comparison Consider the following generic SN2 reaction: If [Nuc:-] were tripled, how would the rate be affected? WHY? Consider the following generic SN1 reaction: Practice with Conceptual Checkpoint 7.13 Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

7.5 SN1 kinetics The structure-rate relationship for SN1 is the opposite of what it was for SN2. To explain this trend, we must examine the mechanism and the reaction coordinate diagram Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

7.5 SN1 – Rationalizing Kinetic Data A carbocation forms during the mechanism. Recall that if a carbocation is more substituted with carbon groups, it should be more stable. Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

7.5 SN1 – Rationalizing Kinetic Data HOW do carbon groups stabilize a carbocation? Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

7.5 SN1 – Rationalizing kinetic data To explain why the 3° substrate will have a faster rate, draw the relevant transition states and intermediates. Primary substrates react too slowly to measure. Practice with SkillBuilder 7.4 Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

7.5 SN1 – stereochemistry For the pure SN1 reaction below, predict the product(s). Pay close attention to stereochemistry. Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

7.5 SN1 – stereochemistry The formation of ion pairs can cause inversion to occur slightly more often than retention Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

7.5 SN – stereochemistry Consider the following reaction What accounts for the 35%/65% product ratio? Is the reaction reacting more by SN1 or SN2? What happened to the Cl atom? Practice with SkillBuilder 7.5 Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

7.5 SN – summary Klein, Organic Chemistry 2e Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

7.6 SN1 Complete Mechanisms In SN1, proton transfer steps often occur before the substitution process. Why would a proton transfer sometimes be necessary before the substitution reaction? For example… If the OH is protonated first though… Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

7.6 SN1 Complete Mechanisms Would it also be helpful to protonate an OH group in an SN2 substitution? Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

7.6 SN1 Complete Mechanisms Lets look at the complete mechanism. Practice with conceptual checkpoint 7.18 Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

7.6 SN1 Complete Mechanisms In SN1, proton transfer steps often occur after the substitution process. Examine the following example The leaving group is good, but what about the nucleophile? Draw a complete mechanism. Each step is an equilibrium. Which side will the equilibrium favor? If the nucleophile were used as the solvent (a solvolysis reaction), would that shift the equilibrium one way or the other? Practice with Conceptual Checkpoint 7.19 Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

7.6 SN1 Complete Mechanisms Rearrangements sometimes occur In SN1 reactions Example: After the leaving group leaves, the resulting carbocation may rearrange. What type of rearrangements are likely? WHY? Predict the product(s), and explain why the carbocation rearrangement is likely to occur before the nucleophile has a chance to attack. Check your work with Conceptual Checkpoint 7.20 Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

7.6 SN1 Complete Mechanisms 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 Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

7.6 SN1 Complete Mechanisms Use the considerations from the previous slide to solve this problem Predict the reagents necessary to complete this substitution. Draw a complete mechanism Draw a complete reaction coordinate diagram including drawings for all transition states. Practice more with SkillBuilder 7.6 Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

7.7 SN2 Complete Mechanisms Proton transfer steps occur often in SN2 reactions for the same reasons they occur in SN1 reactions. Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

7.7 SN2 Complete Mechanisms Proton transfer steps occur often in SN2 reactions for the same reasons they occur in SN1 reactions. Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

7.7 SN2 Complete Mechanisms This reaction would be much slower without the proton transfers. WHY? Qualitatively, will the enthalpy and entropy changes favor the products or the reactants? Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

7.7 SN2 Complete Mechanisms Another example of proton transfer in SN2 Qualitatively, will the enthalpy and entropy changes favor the products or the reactants? Are carbocation rearrangements possible in SN2? Practice with SkillBuilder 7.7 Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

7.8 SN1 vs. SN2 There are four main factors that determine whether a substitution reaction is more likely to occur by SN1 or SN2 Lets examine them in order of importance The substrate (both sterics and the stability of the carbocation) The quality of the leaving group The strength of the nucleophile The solvent Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

7.8 SN1 vs. SN2 Before we can examine carbocation stability, let’s review some terminology ad learn some new Vinyl Allyl Let’s learn some new terminology Benzyl Aryl Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

7.8 Carbocation Stability The stability of the resulting carbocation If a relatively stable carbocation can form when the leaving group leaves, the mechanism may be SN1 What factors affect the stability of carbocations? INDUCTION – already discussed RESONANCE – example… Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

7.8 Carbocation Stability The resonance for allylic and benzylic carbocations is illustrated below Are allylic and benzylic halides more likely to undergo SN1 or SN2? Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

7.8 Carbocation Stability & Sterics Consider whether vinyl and aryl halides are likely to undergo substitution Can you make a steric argument? Can you make a carbocation stability argument? Practice with Conceptual Checkpoint 7.26 Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

7.8 SN1 vs. SN2 (the nucleophile) The quality of the nucleophile What makes a nucleophile strong or weak? Stability (induction, resonance, solvation) Sterics Give some examples of strong nucleophiles and some examples of weak ones Will a strong nucleophile favor SN1 or SN2? WHY? Practice with Conceptual Checkpoint 7.27 Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

7.8 SN1 vs. SN2 (the leaving group) What makes a leaving group good or bad? Stability once it has left WITH a pair of electrons (induction, resonance, solvation) Solvation Give some examples of bad leaving groups and some examples of good ones (figure 7.28 in the text) If the leaving group is too bad, then the substitution can’t take place by either SN1 or SN2. For example… Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

7.8 SN1 vs. SN2 (the leaving group) The most commonly used leaving groups are halides and sulfonate ions. What makes sulfonate ions such good leaving groups? Practice with Conceptual Checkpoint 7.28 Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

7.8 SN1 vs. SN2 (the nucleophile) A stronger nucleophile favors SN2 , although it may react by SN1 if the substrate and is sterically hindered and the leaving group is good. A weaker nucleophile favors SN1, although it may react by SN2 if the substrate cannot stabilize a carbocation effectively, and the leaving group is poor. What factors make nucleophiles strong versus weak? Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

7.8 SN1 vs. SN2 (the solvent) The solvent The solvent surrounds each species in the mechanism including the transition state. How does that help to facilitate the reaction? See next slide Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

7.8 SN1 vs. SN2 (the solvent) The solvent ( ) surrounds each species in the mechanism including the transition state Consider how the energy diagram would be different with a polar versus a nonpolar solvent δ+ δ- δ- δ+ δ- δ+ Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

7.8 SN1 vs. SN2 (the solvent) To specifically promote SN2, what role should the solvent play? The solvent should facilitate the collision between the nucleophile and the electrophile. Is it possible that the solvent could interfere with that key collision? What type of solvent would you choose to accomplish this role? Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

7.8 SN1 vs. SN2 (the solvent) Will this reaction be SN1 or SN2? What do the highlighted red solvents have in common that makes them better than the others? Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

7.8 Promoting SN2 (the solvent) To promote an SN2, use a polar, aprotic solvent such as DMSO or acetonitrile Polar aprotic solvents can stabilize the counter-ion of the nucleophile leaving the nucleophile mostly naked and ready to attack the electrophile. Ready to attack! Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

7.8 Promoting SN2 (the solvent) Because a polar, aprotic solvent will not effectively solvate the nucleophile, the nucleophile is less stable and starts with a high potential energy The activation energy will be lower and the reaction faster Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

7.8 Promoting SN1 (the solvent) To promote an SN1, use a polar, protic solvent The protic solvent will Hydrogen bond with the nucleophile stabilizing it while the leaving group leaves first. Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

7.8 Promoting SN1 (the solvent) A polar, protic solvent will also stabilize the full and partial charges that form during the SN1 mechanism Practice with Conceptual Checkpoint 7.29 Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

7.8 Solvent Effect on Halide Nucleophiles Consider the nucleophiles, F-, Cl-, Br-, and I- In a polar, protic solvent, which should be most reactive? WHY? In a polar, aprotic solvent, which should be most reactive? WHY? Why does the size of the halide affect its ability to attract a polar protic solvent? Practice with SkillBuilder 7.8 Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

7.9 Designing Syntheses How do we use what we have learned to set up successful reactions? We must choose appropriate substrate, nucleophile, leaving group, solvent, etc. If you are working with a 1° substrate, the reaction will be SN2, so what are the best conditions? Nucleophile? Leaving Group? Solvent? Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

7.9 Designing Syntheses If you are working with a 3° substrate, the reaction will be SN1, so what are the best conditions? Nucleophile? Leaving Group? Solvent? Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

7.9 Designing Syntheses If you are working with a 2° substrate, the reaction could be SN1 or SN2, so what are the best conditions to get the stereochemistry you want, and WHY? Nucleophile? Leaving Group? Solvent? Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

7.9 Designing Syntheses Some options and choices: Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

7.9 Designing Syntheses Design a synthesis for the following molecule starting from 2-chlorobutane Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

7.9 Designing Syntheses Sometimes its advantageous to convert a poor –OH leaving group into a OTs rather than a water. See the following example and explain why. Describe appropriate conditions for the following transformation Practice with SkillBuilder 7.9 Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

Additional Practice Problems Give reasonable names for the following molecules Label each halide as primary, secondary, or tertiary Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

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 Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

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 Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

Additional Practice Problems Propose reaction conditions and give a complete mechanism for the following substitution reaction Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

Additional Practice Problems Give a complete mechanism for the following substitution reaction Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e