* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download TOPIC 6. NUCLEOPHILIC SUBSTITUTIONS (chapter 6 and parts of
Elias James Corey wikipedia , lookup
Woodward–Hoffmann rules wikipedia , lookup
Enantioselective synthesis wikipedia , lookup
Discodermolide wikipedia , lookup
1,3-Dipolar cycloaddition wikipedia , lookup
Physical organic chemistry wikipedia , lookup
Marcus theory wikipedia , lookup
Diels–Alder reaction wikipedia , lookup
Tiffeneau–Demjanov rearrangement wikipedia , lookup
Wolff rearrangement wikipedia , lookup
Baylis–Hillman reaction wikipedia , lookup
Vinylcyclopropane rearrangement wikipedia , lookup
Ring-closing metathesis wikipedia , lookup
Hydroformylation wikipedia , lookup
Wolff–Kishner reduction wikipedia , lookup
Ene reaction wikipedia , lookup
George S. Hammond wikipedia , lookup
Strychnine total synthesis wikipedia , lookup
Stille reaction wikipedia , lookup
Petasis reaction wikipedia , lookup
L 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) 2. Discuss the effect of starting material (substrate), leaving group, reagent (a nucleophile) and reaction conditions on the course of a reaction 3. Recognize functional group transformations and synthesis of new molecules in one step by substitution of an appropriate material 4. Explore the substitution chemistry of alcohols and ethers D.M. Collard 2007 REACTIONS TO DATE b su it st io ut Substn C C n d n Ad im El H2/Pt H C C Substn H C C Addn Elimn ns H Br n Substn Subst H ns t io di ad C C OH b su it st io ut ns Acid-Base Chemistry RCOOH + R3N RCOO + R3NH S:6.1-6.5 OVERVIEW: NUCLEOPHILIC SUBSTITUTIONS Cl Br Br Cl S CN KCN NaC C H C C KCl NaBr H NaN3 Cl H2O HO S OH 2 HCl D.M. Collard 2007 C L C Nu Nu L We are only considering sp3 (alkyl) substrates in this section. Molecules with leaving groups on sp2 (e.g., vinyl, aryl) or sp (ethynyl) carbons do not react in fashion described in this section Nucleophiles Donate a pair of electrons: to an electrophile (lone pair or pi bond) Neutral H2O Anionic HO H2C CH2 Electrophiles Receive a pair of electrons: from a nucleophile Cationic C Lacks an octet Cl Cl Al Cl Polar, electrophilic C X D.M. Collard 2007 Effect of Leaving Groups on Electrophilicity C L Nu C Nu L 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 Substitution: What is the Mechanism? substitute /’sêb-,stê,t(y)üt/ vb: to put in the place of another What are the rules? D.M. Collard 2007 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. 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) S:6.6-6.8 Prob: 6.13-15, 17aj,25,27, 31,33,36 Examples D.M. Collard 2007 CH3CH2 Br + Na O CH3 I + Na S CH3 CH3CH2 O S CH3 CH3 Kinetics CH3CH2Br + NaOMe [CH3CH2Br] [NaOMe] 0.01 M 0.02 M 0.01 M 0.02 M 0.01 M 0.01 M 0.02 M 0.02 M CH3CH2OMe + NaBr relative rate 1 2 2 4 Conclusion: Rate = k[R-L][Nu] d1 Mechanism of Nucleophilic Substitution of 1° Alkyl Halides: The SN2 Reaction D.M. Collard 2007 Slide 15 d1 d-laptop, 8/6/2007 Chirality Chiral R-L forms R-Nu with opposite stereochemistry (inversion of stereochemistry, “Walden Inversion”) CH3 H D Br OH CH3 H D OH Interpretation: Nu L Nucleophilicity Basicity and nucleophilicity are not the same, but they are related phenomena A negatively charged nucleophile is more reactive than its conjugate acid. ¯CN > HCN ¯ OH > H O RO¯ > ROH 2 In a group of nucleophiles in which the nucleophilic atom is the same, nucleophilicity parallels trends in basicity. RO¯ > HO¯ >> RCO2¯ >> ROH > H2O Steric bulk hinders nucleophilicity CH3O H3C CH3 C O CH3 Across a row in the periodic table, nucleophilicity parallels trends in basicity. CH3¯ > H2N¯ > HO¯ > F¯ NH3 > H2O D.M. Collard 2007 Down a column in the periodic table, trends in nucleophilicity of anions depend on the choice of solvent. polar protic polar aprotic H2O CH3CO2H MeOH EtOH (CH3)2SO – DMSO dimethyl sulfoxide CH3CN – AN actonitrile (CH3)2NCHO – DMF CH3COCH3 CH2Cl2 - THF N,N-dimethylformamide acetone methylene chloride tetrahydrofuran O Et2O – “ether” non-polar diethyl ether CH3(CH2)4CH3 benzene Protic solvents solvate the anions (nucleophiles) by H-bonding and cations (counterions). Small R O H electronegative anions particularly are well solvated, lowering their nucleophilicity. Trends in nucleophilicity in polar protic solvents increases H going down a column of the periodic table O R Polar aprotic solvents cannot hydrogen bond to anions (but do solvate cations). Trends in nucleophilicity in polar aprotic solvents parallels trends in basicity. Large neutral nucleophiles (H2S, PR3) are highly polarizable and can donate more electron density than smaller neutral nucleophiles. D.M. Collard 2007 H H R O R O R O H R R O R O R O R R Nucleophilicity of Anions nucleophilicity ↑ H He Li K Mg Ca C N ¯CH3 ¯NH2 Si P B Al Ge Ga O ¯ OH ¯ SH S As Se ¯ SeH Ne F F¯ Cl Cl¯ Br Br¯ base strength ↑ Na Be Ar Kr I I¯ Relative Nucleophilicity (in MeOH) Relative Nucleophilicity Excellent Nucleophiles CN¯ HS¯ I¯ Good Nucleophiles Fair Nucleophiles Cyanide 126,000 Thiolate 126,000 Iodide 80,000 ¯OH Hydroxide 16,000 Br¯ Bromide 10,000 N3¯ Azide 10,000 NH3 Ammonia 8000 NO2¯ Nitrite 5000 Cl¯ Chloride 1000 CH3COO¯ Acetate 630 F¯ Fluoride 80 CH3OH Methanol 1 Water 1 H2O Nucleophilic relative strength is measured by relative rate in an SN2 reaction (but depends on substrate, solvent type, etc.) D.M. Collard 2007 nucleophilicity in protic solvents ↑ nucleophilicity in APROTIC solvents ↑ base strength ↑ L Leaving Group Ability Rate: -I > -Br > -Cl >> -F C-L bond must be broken – weaker bonds are more polarizable, easier to break Bond strengths (kcal/mole): C-F C-Cl C-Br C-I 116 79 66 52 Overall: A good substrate for bimolecular nucleophilic substitution should have: 1. Weak C-L bond 2. Polarizable C-L bond (ease with which the electron distribution in the bond is distorted) 3. Leaving group that can accommodate a pair of electrons pKa of conjugate acid Leaving group Good Leaving Groups I¯ Iodide Bromide -9 Cl¯ Chloride -7 RSO3¯ H2O Very Poor Leaving Groups Sulfonate -6.5 Water -1.7 F¯ Fluoride 3.2 HS¯ Thiolate 7 ¯CN Cyanide HO¯ Hydroxide RO¯ Alkoxide 16-18 H¯ Hydride 35 2 Amino 38 3 Methyl 48 ¯NH ¯CH D.M. Collard 2007 -10 Br¯ 9.2 15.7 Alkyl Substrates Me Rate: methyl > 1° > 2° ( 3° unreactive) HH Nu Et L H iPr Nu MeMe L tBu Me Adjacent alkyl groups also slow the reaction L L L Energetics of One-Step (i.e., concerted) Reaction SN2 ΔG Reaction coordinate D.M. Collard 2007 Practical Applications of SN2 Reactions: Functional Group Transformations at 1o and 2o Carbons source of nucleophile OH OR R OH R OR ROH R SR RSH SR CN R Hal N3 NR'3 C CH Na OH Na NaH Na OR Na SR R CN Na CN R N3 Na N3 NR'3 R NR'3 R C CH HC CH NaNH2 Intramolecular SN2 Reactions - Cyclizations Br NaOH O OH Br D.M. Collard 2007 NaOH OH Na C CH ~ MAKE FLASHCARDS ~ NaCN Br NC methyl, 1o, and 2o inversion of stereochemistry SN 2 front back Substrate + Reagent (and conditions) Substrate + Reagent (and conditions) Substrate and Product Substrate and Product Reagent (and conditions) and Product Reagent (and conditions) and Product Problem: How would you prepare 2-phenylethanethiol from 1-iodo-2phenylethane? I SH ? Problem: How would you make the following compound from 1bromopropane and any other starting materials? N D.M. Collard 2007 Br 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 Synthesis of Alkynes and Alkanes: Alkylation of Acetylide Anions R C C H NaNH 2 R' R C C Na Br R C C R' H2/cat R CH2 CH2 R' R' must be 1° D.M. Collard 2007 L SUBSTITUTION AT 3° SUBSTRATES: UNIMOLECULAR NUCLEOPHILIC SUBSTITUTION (SN1) S:6.9-6.13 Prob: 6.16,30,35 Example Br H2O OH HBr Experimental observations of kinetics, chirality, substrate structure and effect of nucleophiles for this reaction are inconsistent with the SN2 mechanism Kinetics CH3 H3C Br CH3 H3C H2O OH CH3 CH3 [t-BuBr] [H2O] relative rate 0.01 M 0.02 M 0.01 M 0.02 M 0.01 M 0.01 M 0.02 M 0.02 M 1 2 1 2 Result: Rate = k[R-L] independent of concentration of Nu D.M. Collard 2007 HBr Mechanism of Nucleophilic Substitution of 3° Alkyl Halides: SN1 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 RR S-H Br (protic solvent) R S-H = HOH, RCO2H, ROH D.M. Collard 2007 Substrates Rate: 3° > 2° (1°, methyl not reactive) Interpretation: MeMe L Me Stability of Carbocations H C C H H Carbocation Methyl Ethyl i-Propyl t-Butyl Relative Energy (kcal/mol) 0 -37 -65 -83 - More substituted carbocation stabilized by hyperconjugation Effect of Leaving Group Rate: -I > -Br > -Cl (F: unreactive) MeMe L Me C-L bond must be broken – weaker, polarizable bonds are easier to break Bond strength: C-F > C-Cl > C-Br > C-I Overall: A good substrate for unimolecular nucleophilic substitution should have: 1. Weak C-L bond 2. Polarizable C-L bond (ease with which the electron distribution in the bond is distorted) 3. Leaving group which can accommodate a pair of electrons D.M. Collard 2007 Effect of Nucleophile/Solvent Rate independent of concentration of nucleophile (solvent) Rate depends on polarity of solvent Chirality A single enantiomer of substrate with the leaving group on the stereogenic center reacts to give product that consists of a mixture of both enantiomers. Me PrEt Br H2O PrEt Energetics of a Two-Step Reaction SN1 ΔG Reaction coordinate D.M. Collard 2007 Me Me OH HO EtPr SUMMARY: FACTORS EFFECTING SN1 AND SN2 REACTIONS SN1 S:6.15; Prob: 6.18,26 SN2 Nu H L L Nu H Nu Nu H Nu L Dissociation-Nucleohipic addition-Deprotonation One-step (concerted) mechanism Substrate: 3°>2°>>1°or methyl - Stability of carbocation intermediate Rate = k [substrate] - independent of [nucleophile] - rate depends on solvent polarity Chirality - racemization Generally only useful for solvolyses (reactions with H2O, ROH, RCO2H) Substrate: Methyl>1°>2°>>3° - Steric bulk hinders attack of Nu Rate = k [substrate] [nucleophile] Chirality - Inversion Often performed in polar aprotic solvents, e.g., DMF (Me2NCHO), DMSO (Me2SO) to dissolve substrate and ionic reagent, and increase reaction rate 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) X H L X H L D.M. Collard 2007 L SUBSTITUTION REACTIONS OF ALCOHOLS Alcohols as Acids and Bases R O H R O B R O H A H H R O H Alcohols are weak acids and weak bases. 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! Na Br H3C OH Alcohol + H-Hal 3o Alcohols: SN1 H H Br OH O H D.M. Collard 2007 S:11.6-11.9 1o Alcohols: SN2 H HBr OH O H Other reagents o o (1 or 2 ) R O H o o (1 or 2 ) R O H D.M. Collard 2007 PBr3 SOCl2 R Br R Cl MESYLATES AND TOSYLATES IN SN2 REACTIONS O Cl R O H S R' O O 1o Nu R O S R' O R’ = Me: mesylate (Ms) 4-methylphenyl: tosylate (Ts) R Nu Nu = Hal RS NC etc. Problem: How would you prepare 2-phenylethanethiol from 2-phenyl-1ethanol? OH SH ? Problem: How would you make the following product from 1-propanol and any other starting materials? ? OH D.M. Collard 2007 N + Cl S:11.10 S:11.11-12 SYNTHESIS OF ETHERS Synthesis of Ethers: Williamson Ether Synthesis Overall Reaction and Mechanism 1 or 2o R Br (Cl or I) R O Na Designing Williamson Ether Syntheses You could suggest making either C-O bond of the ether. O O CH3 Br O D.M. Collard 2007 CH3 H3C Br O CH3 Prob: 11.32 Synthesis of Symmetrical Ethers: Dehydration of Alcohols OH H2SO4 140 oC O At higher temperature a competing reaction predominates (elimination of water to form an alkene, see Topic 7) OH H2SO4 180 oC Reaction of Ethers: Acid-catalyzed Hydrolysis R O R' HBr R OH HBr D.M. Collard 2007 + Br R' HBr O O Br Δ CH3 OH HBr Br Δ CH3 L SUBSTITUTIONS IN SYNTHESIS You should prepare a chart of all of the types of reactions that have been covered so far… ….we’ll add more later. tit bs su Br H H2/Pt C C H C C ns Br2, hν io ut H C C H Br im El n Addn Elimn HBr Subst H C C OH t bs u s D.M. Collard 2007 ns it o itu Prob: 6.17,20, 32a-h,33 S:4.18-19 ONE-STEP SYNTHESES It is important to recognize transformations which can be performed in a single step. Use the thought process: - What can the product can be made from? PRODUCT ⇒ STARTING MATERIAL - The synthesis itself is STARTING MATERIAL → PRODUCT Problem: How would you prepare the following from appropriate alkyl chlorides? (a) CH3CH2SH (b) (CH3)2CHCN (c) CH2 C C CH3 D.M. Collard 2007 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. D.M. Collard 2007 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? [An introduction to designing multi-step syntheses] N3 OH from D.M. Collard 2007 Problem: Predict the structure of the product of the following reaction Cl NaOH EtOH C6H10S SH An important limitation on acid catalyzed 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? OH NH3 H2SO4 NH2 Why can’t you do this sequentially? i.e., OH H2SO4 OH2 NH3 NH2 Acid promoted SN2 reactions are limited to cases where the nucleophile is very weakly basic (i.e., reaction with H-Hal). For other nucleophiles, convert the alcohol to the tosylate or mesylate first. D.M. Collard 2007 The role of nucleophilicity, leaving group ability, and substrate on SN processes. Which of the following proceed efficiently? H3C Br Br OH H2O H2O NaBr H2O H3C Br NaOH H2O OH Br NaOH H2O OH Br OH HBr H2O Br H3C OH OH Br H3C OH Br OH NaOH H2O HBr H2O What about secondary alkyl halides? 1° R-L: 3° R-L: 2° R-L: might display features of both SN1 and SN2 reactions (!) Under conditions strongly favoring SN1 reactions ⇒ SN1 Under conditions strongly favoring SN2 reactions ⇒ SN2…. …..but strongly basic nucleophiles promote elimination! (see Topic 7) What about vinyl halides and aryl halides? D.M. Collard 2007 TOPIC 6 ON EXAM 3 Types of Questions - 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 D.M. Collard 2007