7.1 Introduction to Substitution Reactions. 7.1 Introduction to Substitution Reactions. Reactions. 7.2 Alkyl Halides. Reactions

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1 7.1 Introduction to Substitution Reactions One group of atoms is replaced with another. Generic example: 7.1 Introduction to Substitution Reactions Which side do you think will be favored in the dynamic equilibrium? Specific example: Draw a reaction coordinate diagram that illustrates your equilibrium prediction. Label the nucleophile and the electrophile Introduction to 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. O + O 7.1 Introduction to Substitution Reactions Some leaving groups encourage a substitution better than others. A good leaving group must: 1. Create a positive charge to attract the nucleophile: The electronegative leaving group creates a partial charge on the site of attack to attract the negative charge of the nucleophile. 2. Be able to stabilize the electrons it leaves with: Introduction to Substitution Reactions Can you give some examples of groups of atoms that qualify as good leaving groups according to the two key criteria? 1. Create a positive charge to attract the nucleophile. 2. Be able to stabilize the electrons it leaves with. 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: 1. Identify and name the parent chain. 2. Identify the name of the substituents (side groups). 3. Assign a locant (number) to each substituent. 4. Assemble the name alphabetically. The halide group is the key substituent we will name and locate

2 7.2 Alkyl Halides Nomenclature For each of these examples, convince yourself that they are numbered in the most appropriate way. 7.2 Alkyl Halides 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 Halides Nomenclature Give reasonable names for the following molecules: Cl Cl Try more examples with CONCEPTUAL CHECKPOINT Alkyl Halides Structure Greek letters are often used to label the carbons of the alkyl group attached to the halide: Substitutions occur at the alpha carbon. The amount of branching at the alpha carbon affects the reaction mechanism. There are three types of alkyl halides: R H Alkyl Halides Structure Alkyl halides are often toxic. Some 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. 7.2 Alkyl Halides 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

3 7.2 Alkyl Halides Structure HOW does a molecule s structure affect its function and properties? 7.3 Possible Mechanisms for Substitution Reactions Recall from Chapter 6 the arrow pushing patterns for ionic processes: Possible Mechanisms for Substitution Reactions Recall from Chapter 6 the arrow pushing patterns for ionic processes: 7.3 Possible Mechanisms for Substitution Reactions EVERY nucleophilic substitution reaction will involve nucleophilic attack and the loss of a leaving group The order in which these steps occur can vary. The inclusion of a proton transfer or rearrangement can also vary Possible Mechanisms for Substitution Reactions Draw mechanisms for each possibility and critique their likelihood: 1. Nucleophilic attack first, then loss of leaving group 2. Loss of leaving group first, then nucleophilic attack 3. Both nucleophilic attack and loss of leaving group happen simultaneously Practice arrow pushing with SKILLBUILDER S N 2 Mechanism How might you write a rate law for this reaction? What type of experiment could you run in the lab to test whether this mechanism is possible? Test yourself with CONCEPTUAL CHECKPOINT

4 7.4 S N 2 Stereochemistry What do the S, N, and 2 stand for in the S N 2 name? How might we use stereochemistry to support the S N 2 mechanism for the following reaction? 7.4 S N 2 Backside Attack The nucleophile attacks from the backside: The backside is less hindered with electron density. The nucleophile must approach the backside to allow proper orbital overlap that is necessary for bonding. Practice drawing S N 2 reactions with SKILLBUILDER S N 2 Backside Attack Draw the transition state for the following reaction. Use extended dotted lines to represent bonds breaking and forming. 7.4 S N 2 Kinetics Less sterically hindered electrophiles react more readily under S N 2 conditions. Practice drawing transition states with SKILLBUILDER To explain this trend, we must examine the reaction coordinate diagram S N 2 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? 7.4 S N 2 Rationalizing Kinetic Data Which reaction will have the fastest rate of reaction? H 3 C Nuc: X H 3 C H substrates react too slowly to measure. 7-24

5 7.4 S N 2 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? 7.4 S N 2 Rationalizing Kinetic Data If you memorize the rules, you will probably miss questions about exceptions to the rules. It is better to understand the concepts than to memorize the rules. Should neopentyl bromide react by an S N 2 reaction relatively quickly or relatively slowly? S N 1 A Stepwise Mechanism 7.5 S N 1 A Stepwise Mechanism What do the S, N, and 1 stand for in the S N 1 name? If kinetic experiments were performed to determine the rate law, you would find that: S N 1 Kinetics 7.5 S N 1 Reaction Coordinate In a multistep mechanism, one step will be the slowest. The slow step is the rate determining step (RDS). Let s consider a simple example. Which step determines how frequently the sand moves from the top of the hourglass to the bottom?

6 7.5 S N 1 Reaction Coordinate Which step is the RDS and Why does the rate depend only on [electrophile] and NOT [nucleophile]? 7.5 S N 1 vs. S N 2 Comparison Consider the following generic S N 2 reaction: If [Nuc: ] were tripled, how would the rate be affected? Consider the following generic S N 1 reaction: If [Nuc: ] were tripled, how would the rate be affected? Practice with CONCEPTUAL CHECKPOINT S N 1 Kinetics The structure rate relationship for S N 1 reactions is the opposite of what it is for S N 2 reactions. 7.5 S N 1 Rationalizing Kinetic Data A carbocation forms during the mechanism. To explain this trend, we must examine the mechanism and the reaction coordinate diagram. Recall that if a carbocation is more substituted with carbon groups, it should be more stable S N 1 Rationalizing Kinetic Data 7.5 S N 1 Rationalizing Kinetic Data To explain why the 3 substrate will have a faster rate, draw the relevant transition states and intermediates. HOW do carbon groups stabilize a carbocation? Primary substrates react too slowly to measure. Practice with SKILLBUILDER

7 7.5 S N 1 Stereochemistry For the pure S N 1 reaction below, predict the product(s). Pay close attention to stereochemistry. 7.5 S N 1 Stereochemistry Consider the following reaction: What accounts for the 35%/65% product ratio? Is the reaction reacting more by S N 1 or S N 2? What happened to the Cl atom? Practice with SKILLBUILDER S N Summary 7.6 Drawing the Complete Mechanism In S N 1, 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: Drawing the Complete Mechanism Would it also be helpful to protonate an OH group in an S N 2 substitution? 7.6 Drawing the Complete Mechanism Let s look at the complete mechanism. Practice with CONCEPTUAL CHECKPOINT

8 7.6 Drawing the Complete Mechanism In S N 1, proton transfer steps often occur after the substitution process. Examine the following example: 7.6 Drawing the Complete Mechanism Rearrangements sometimes occur in S N 1 reactions. For 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 After the leaving group leaves, the resulting carbocation may rearrange. What type of rearrangements are likely? 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 Drawing the Complete Mechanism 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 S N 1 or S N 2? 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? S N 1=racemization while S N 2=inversion Drawing the Complete Mechanism Use the considerations from the previous slide to solve this problem: 1. Predict the reagents necessary to complete this substitution. 2. Draw a complete mechanism. 3. Draw a complete reaction coordinate diagram including drawings for all transition states. Practice more with SKILLBUILDER Drawing the Complete Mechanism of an S N 2 Reaction Proton transfer steps occur often in S N 2 reactions for the same reasons they occur in S N 1 reactions. 7.7 Drawing the Complete Mechanism of an S N 2 Reaction This reaction would be much slower without the proton transfers

9 7.7 Drawing the Complete Mechanism of an S N 2 Reaction Will this equilibrium probably favor reactants or products? 7.7 Drawing the Complete Mechanism of an S N 2 Reaction Another example of proton transfer in S N 2: 7-49 Will this equilibrium probably favor reactants or products? Are carbocation rearrangements possible in S N 2? Practice with SKILLBUILDER S N 1 vs. S N 2 Determining Which Mechanism Predominates In our earlier discussions, we discussed two factors that determine whether a reaction will be S N 1 or S N 2: 1. Steric hindrance at the electrophilic site 2. The stability of the resulting carbocation There are two other important factors to consider: 3. The quality of the nucleophile 4. The solvent Let s examine factors 2, 3, and 4 in detail. Before we can examine carbocation stability, let s review some terminology: 1. Vinyl 2. Allyl 7.8 S N 1 vs. S N 2 Carbocation Stability Let s learn some new terminology: 1. Benzyl 2. Aryl S N 1 vs. S N 2 Carbocation Stability 2. The stability of the resulting carbocation: If a relatively stable carbocation can form when the leaving group leaves, the mechanism may be S N 1. What factors affect the stability of carbocations? INDUCTION already discussed RESONANCE for example: 7.8 S N 1 vs. S N 2 Carbocation Stability The resonance for allylic and benzylic carbocations is illustrated below: Are allylic and benzylic halides more likely to undergo S N 1 or S N 2?

10 7.8 S N 1 vs. S N 2 Carbocation Stability & Sterics Consider whether vinyl and aryl halides are likely to undergo substitution: 7.8 S N 1 vs. S N 2 The Nucleophile 3. 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. Can you make a steric argument? Can you make a carbocation stability argument? Practice with CONCEPTUAL CHECKPOINT Will a strong nucleophile favor S N 1 or S N 2? Practice with CONCEPTUAL CHECKPOINT S N 1 vs. S N 2 The Leaving Group What makes a leaving group good or bad? Stability once it has left WITH a pair of electrons (induction, resonance, 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 S N 1 or S N 2. For example: 7.8 S N 1 vs. S N 2 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 S N 1 vs. S N 2 The Solvent 7.8 S N 1 vs. S N 2 The Solvent 4. The solvent ( ) surrounds each species in the mechanism, including the transition state: 4. 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. Consider how the energy diagram would be different with a polar versus a nonpolar solvent. H R H Nuc LG

11 7.8 S N 1 vs. S N 2 The Solvent To specifically promote S N 2, 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? 7.8 S N 1 vs. S N 2 The Solvent Will this reaction be S N 1 or S N 2? What type of solvent would you choose to accomplish this role? What do the highlighted red solvents have in common that makes them better than the others? S N 1 vs. S N 2 The Solvent Promoting S N 2 To promote an S N 2, use a polar, aprotic solvent, such as DMSO or acetonitrile. Polar aprotic solvents can stabilize the counterion of the nucleophile, leaving the nucleophile mostly naked and ready to attack the electrophile. Ready to attack! 7.8 S N 1 vs. S N 2 The Solvent Promoting S N 2 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 S N 1 vs. S N 2 The Solvent Promoting S N 1 To promote an S N 1 reaction, use a polar, protic solvent: The protic solvent will hydrogen bond with the nucleophile, stabilizing it, while the leaving group leaves first. 7.8 S N 1 vs. S N 2 The Solvent Promoting S N 1 A polar, protic solvent will also stabilize the full and partial charges that form during the S N 1 mechanism. Practice with CONCEPTUAL CHECKPOINT

12 7.8 S N 1 vs. S N 2 Solvent Effect on Halide Nucleophiles Consider the nucleophiles F, Cl, Br, and I. In a polar, protic solvent, which should be most reactive? In a polar, aprotic solvent, which should be most reactive? Why does the size of the halide affect its ability to hydrogen bond? Practice with SKILLBUILDER Selecting Reagents to Accomplish Functional Group Transformation How do we use what we ve learned to set up successful reactions? We must choose an appropriate substrate, nucleophile, leaving group, solvent, etc. If you are working with a 1 substrate, the reaction will be S N 2, so what are the best conditions? Nucleophile? Leaving Group? Solvent? Selecting Reagents to Accomplish Functional Group Transformation If you are working with a 3 substrate, the reaction will be S N 1, so what are the best conditions? Nucleophile? Leaving Group? Solvent? 7.9 Selecting Reagents to Accomplish Functional Group Transformation If you are working with a 2 substrate, the reaction could be S N 1 or S N 2, so what are the best conditions to get the stereochemistry you want, and Nucleophile? Leaving Group? Solvent? Selecting Reagents to Accomplish Functional Group Transformation Some options and choices: 7.9 Selecting Reagents to Accomplish Functional Group Transformation 1. Design a synthesis for the following molecule starting from (R) 2 chlorobutane. 1. Describe appropriate conditions for the following transformation. Practice with SKILLBUILDER