L18 TOPIC 6. NUCLEOPHILIC SUBSTITUTIONS (chapter 6 and parts of chapter 11)

OBJECTIVES 1. Describe two pathways (mechanisms) to account for substitution at sp3 carbons bearing an electronegative atom (leaving group) Discuss the effect of starting material (substrate), leaving group, reagent (a nucleophile) and reaction conditions on the course of a reaction Recognize functional group transformations and synthesis of new molecules in one step by substitution of an appropriate material Explore the substitution chemistry of alcohols and ethers

REACTIONS TO DATE Acid-Base Chemistry

OVERVIEW: NUCLEOPHILIC SUBSTITUTIONS

PRS

Nucleophiles Electrophiles Donate a pair of electrons: to an electrophile (lone pair or pi bond) Neutral Anionic Electrophiles Receive a pair of electrons: from a nucleophile Cationic Lacks an octet Polar, electrophilic

PRS Effect of Leaving Groups on Electrophilicity C-L bond must be polarizable C-L bond must be relatively weak L needs to be able to accommodate a pair of electrons  Good leaving groups are weak bases PRS

Substitution: What is the Mechanism? substitute /’sêb-,stê,t(y)üt/ vb: to put in the place of another What are the rules?                                                                                                                                             

TWO CLASSES OF REACTION Substitution reactions can be performed under different conditions which give rise to dramatically different outcomes. Nucleophilic substitution reactions can be classified as one of two types, based on these experimental observations. Characteristics which allow this classification are listed on the next slide, and will be studied in greater detail in the next two sections. In order to develop predictive tools, we need to understand reasons why these observations are important. That is, we need to develop proposals for two different mechanisms which are consistent with the two sets of data and which we can use to predict the outcome of other reactions.

SUBSTITUTION AT 1° SUBSTRATES: BIMOLECULAR NUCLEOPHILIC SUBSTITUTION (SN2) Prob: 6.13-15, 17a-j,25,27, 31,33,36 Examples

Experimental Observations Kinetics [CH3CH2Br] [NaOMe] relative rate 0.01 M 0.01 M 1 0.02 M 0.01 M 2 0.01 M 0.02 M 2 0.02 M 0.02 M 4 Conclusion: Rate = k[R-L][Nu] Interpretation:

Chirality Chiral R-L forms R-Nu with opposite stereochemistry (inversion of stereochemistry, “Walden Inversion”) Interpretation:

PRS PRS HWeb Effect of Nucleophile Rate: I– > OH– > Br– > Cl– > F– > H2O Interpretation: PRS PRS HWeb

Effect of Leaving Group Rate: -I > -Br > -Cl >> -F C-L bond must be broken – weaker bonds are easier to break Bond strengths (kcal/mole): C-F 116 C-Cl 79 C-Br 66 C-I 52 Interpretation: A good substrate for bimolecular nucleophilic substitution should have: Weak C-L bond Polarizable C-L bond (ease with which the electron distribution in the bond is distorted) Leaving group which can accommodate a pair of electrons L19

Effect of Substrate Rate: methyl > 1° > 2° ( 3° unreactive) Adjacent alkyl groups also slow the reaction

Conclusion Bimolecular nucleophilic substitution mechanism explains the observations Effect on rate: Nu: L: C-L: R-L: R

Energetics of One-Step (i.e., concerted) Reaction SN2 DG Reaction coordinate

Effect of Solvent on SN2 Reactions Generally need a polar solvent to dissolve the source of the nucleophile (i.e., a salt of an anionic nucleophile). However, protic solvents solvate anionic nucleophiles, lowering their reactivity. Thus, polar aprotic solvents are soften used. Such as DMSO, DMF, CH3CN, THF, Et2O. Anionic Nucleophile: Solvent polarity  enhances stability of  rate Neutral Nucleophile: ‡ ‡

Common Solvents in Organic Chemistry H2O HCO2H MeOH EtOH (CH3)2SO - DMSO CH3CN - AN (CH3)2NCHO - DMF CH3COCH3 CH2Cl2 - THF Et2O – “ether” CH3(CH2)4CH3

Practical Applications of SN2 Reactions: Functional Group Transformations at 1o and 2o Carbons

Problem: How would you prepare 2-phenylethanethiol from 1-iodo-2-phenylethane? Problem: How would you make the following compound from 1-bromopropane and any other starting materials?

(a) Ph3N or Ph3P (b) 1.0 M CH3ONa or 2.0 M CH3ONa Problem: Which of the following would undergo the fastest reaction with 1-bromopropane? (a) Ph3N or Ph3P (b) 1.0 M CH3ONa or 2.0 M CH3ONa

HWeb Synthesis of Alkynes and Alkanes: Alkylation of Acetylide Anions (see also 4.17c) HWeb

L20 SUBSTITUTION AT 3° SUBSTRATES: UNIMOLECULAR NUCLEOPHILIC SUBSTITUTION (SN1) S:6.9-6.13 Prob: 6.16,30,35 Example Experimental observations of kinetics, chirality, substrate structure and effect of nucleophiles for this reaction are inconsistent with the SN2 mechanism

Experimental Observations Kinetics Result: Rate = k[R-L] independent of concentration of Nu Interpretation: [t-BuBr] [H2O] relative rate 0.01 M 0.01 M 1 0.02 M 0.01 M 2 0.01 M 0.02 M 1 0.02 M 0.02 M 2

Effect of Substrate Rate: 3° > 2° (1°, methyl not reactive) Interpretation: Stability of Carbocations Carbocation Relative Energy (kcal/mol) Methyl 0 Ethyl -37 i-Propyl -65 t-Butyl -83

Effect of Leaving Group Rate: -I > -Br > -Cl (F: unreactive) C-L bond must be broken – weaker bonds are easier to break Bond strength: C-F > C-Cl > C-Br > C-I Interpretation: A good substrate for unimolecular nucleophilic substitution should have: Weak C-L bond Polarizable C-L bond (ease with which the electron distribution in the bond is distorted) Leaving group which can accommodate a pair of electrons S:6.13E

S:6.13B Effect of Nucleophile Concentration of nucleophile (see slide on experimental observations) Identity of nucleophile Rate of reaction: I- = Br- = Cl- Interpretation:

Chirality Optically active R-L forms racemic R-Nu S:6.12A

Summary Unimolecular nucleophilic substitution mechanism explains the observations. Effect on rate: Nu: L: C-L: Chirality: Substrate: Solvent polarity: PRS

Energetics of a Two-Step Reaction SN1 DG Reaction coordinate PRS

PRS Practical Applications of SN1 Reactions: Solvolysis The only practical SN1 reactions are solvolyses, reactions in which the solvent also acts as the nucleophile. These reactions arise because solvents which are polar enough to facilitate dissociation of the substrate are also nucleophilic S-H = HOH, RCO2H, ROH Effect of Solvent Polarity Increasing solvent polarity dramatically increases rate of reaction by facilitating disocciation of substrate into carbocation and anion (leaving group). PRS

SUMMARY: FACTORS EFFECTING SN1 AND SN2 REACTIONS Prob: 6.18,26 SN1 Substrate: 3°>2°>>1°or methyl - Stability of carbocation intermediate Nu: No effect - Nu not involved in RDS Rate increases by use of polar solvents - Enhanced rate of ionization Chirality -Racemization Generally only useful for solvolyses (reactions with H2O, ROH, RCO2H) Unimolecular kinetics SN2 Substrate: Methyl>1°>2°>>3° - Steric bulk hinders attack of Nu Rate depends on type of Nu - Nu involved in RDS Chirality -Racemization Rate a [nucleophile] Often performed in polar aprotic solvents, e.g., DMF (Me2NCHO), DMSO (Me2SO) to dissolve substrate and ionic reagent, and increase reaction rate Bimolecular kinetics

Why is Nucleophilic Substitution Limited to sp3 (Alkyl) Substrates? Inaccessible carbon atom Unstable sp2 carbocation (hinders SN2) (hinders SN1)

HWeb A Limitation to Reactions of Alkyl Halides with Nucleophiles Elimination competes with substitution if the nucleophile is too basic or if the electrophile is too crowded (we will explore this further in Topic 7) HWeb

SUBSTITUTION REACTIONS OF ALCOHOLS Alcohols as Acids and Bases Alcohols are weak acids and weak bases. However, acid-base chemistry is important in activating the electrophilic and nucleophilic character of alcohols, respectively.

Conversion Of Alcohols To Alkyl Halides Alcohols do not react with sodium halides to give alkyl halides! Alcohol + H-Hal 3o Alcohols: SN1

1o Alcohols: SN2

Other reagents

MESYLATES AND TOSYLATES IN SN2 REACTIONS R’ = Me: mesylate (Ms) 4-methylphenyl: tosylate (Ts)

Problem: How would you prepare 2-phenylethanethiol from 2-phenyl-1-ethanol? Problem: How would you make the following product from 1-propanol and any other starting materials?

SYNTHESIS AND REACTIONS OF ETHERS Prob: 11.32 Synthesis of Ethers: Williamson Ether Synthesis Overall Reaction and Mechanism

PRS Designing Williamson Ether Syntheses You could suggest making either C-O bond of the ether. PRS

Synthesis: Dehydration of Alcohols At higher temperature a competing reaction predominates (elimination of water to form an alkene, see Topic 7)

Acid Catalyzed Hydrolysis of Ethers

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A note on the use of alcohols in SN reactions tert-butanol must be protonated to make the hydroxyl group a better leaving group Ammonia is nucleophilic So why doesn’t this reaction work?

SUBSTITUTIONS IN SYNTHESIS L22 Prob: 6.17,20, 32a-h,33 You should prepare a chart of all of the types of reactions that have been covered so far… ….we’ll add more later.

ONE-STEP SYNTHESES S:4.18-4.19 It is important to recognize transformations which can be performed in a single step. Problem: How would you prepare the following from appropriate alkyl chlorides? (a) CH3CH2SH (b) (CH3)2CHCN

(c) from starting materials with 7 or fewer carbon atoms

Problem: Why does the following reaction not take place? CH3CH2CH3 + HO— CH3CH2CH2OH + H—

Problem: Explain why reaction of 1-bromopropane with potassium cyanide gives a mixture of CH3CH2CH2CN (major product) and CH3CH2CH2NC (minor)? Draw Lewis structures of the products and nucleophiles.

Problem: How can you prepare the following two compounds from the appropriate alkyl bromide? (a) Methyl phenyl ether, Me-O-Ph (b) (S)-2-Pentanol, CH3CH(OH)CH2CH2CH3

Problem: How could you perform the following synthesis Problem: How could you perform the following synthesis? [An introduction to designing multi-step syntheses] from

Problem: Predict the structure of the product of the following reaction PRS PRS PRS

HWeb TOPIC 6 ON EXAM 3 Types of Questions Preparing for Exam 3 - Recognize factors which influence the mechanism of nucleophilic substitutions - Predict outcomes of substitution reactions - The problems in the book are good examples of the types of problems on the exam. Preparing for Exam 3 - Work as many problems as possible. - Work in groups. - Do the “Learning Group Problem” at the end of the chapter. - Work through the practice exam HWeb

PRS Which of the following are primary or secondary alkyl halides, which undergo nucleophilic substitution reactions? 1 only B, C, D, F and G 2 only C, D, F and G 3 only C and D 4 only C, D and G 5 only B and E PRS

PRS Which of the following is the best leaving group in a nucleophilic substitution reaction? 1 2 3 4 5 PRS

PRS Which of the following would undergo the most rapid acidolysis (e.g., substitution with acetic acid)? 1 (CH3)3CBr 2 (CH3)3CF 3 CH3Cl 4 (CH3)3CCl 5 CH3CH2Br PRS

PRS Which of the following reaction profiles corresponds to the fastest overall reaction? 1 2 3 4 Energy Reaction Coordinate PRS

PRS If the nucleophile is used as the solvent in an SN1 reaction with tert-butyl bromide, which of the following will react fastest? 1 water, H2O 2 methanol, CH3OH 3 ethanol, CH3CH2OH 4 formic acid, HCOOH PRS

PRS Which of the following is the most reactive electrophile in SN2 reactions? 1 2 PRS

PRS Which of the following reagents does not convert primary alcohols into alkyl halides? 1 HBr 2 SOCl2 3 PBr3 4 NaBr ? PRS

PRS What is the product of the reaction between (R)-2-bromopentane and potassium cyanide? 1 2-pentylpotassium 2 (2R,3S)-2-bromo-3-cyanopentane 3 trans 2-pentene 4 (S)-2-cyanopentane PRS

PRS Which statement is true regarding stereochemistry of SN1 and SN2 reactions? 1 Stereochemistry is inverted in SN2 and racemized in SN1. 2 Stereochemistry is racemized in SN2 and inverted in SN1 3 Stereochemistry is retained in SN2 and inverted in SN1. 4 Stereochemistry is retained in SN2 and racemized in SN1. PRS

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