Chem 43-6311, ch8-physical-organic-sykes-co-addition.docx 2016January17 page 1 Addition to carbonyl compounds (skip 8.25, Me3SiCN, 8.2.7, 8.4.5-7, 8.5, 8.7 1. general properties HA O 1.1. significant CO dipole attracts Lewis acids and bases 1.1.1. lone pairs and partial charge at oxygen H3 C CH3 1.1.2. polarized electrons readily displaced toward oxygen A 1.1.3. planar electrophile (3 sp2 hybridized orbitals), easy access 1.1.4. addition results in rehybridization (4 sp3 orbitals), brings substituents closer together 1.2. unactivated carbonyl reacts with good nucleophiles 1.2.1. RS-, CN-, RLi, RMgBr, RO-, RNH2 1.2.2. Acids activate carbonyl but deactivate basic nucleophile 1.3. Lewis acid required for weak nucleophiles 1.3.1. ROH, RSH, arene, PhNH2 O H O AlCl3 H OR H3C H3C CH3 O Cl H3C HOR CH3 1.3.2. hydrogen bonding in protic solvent weakly activates 1.4. Carbonyl is activated by electron withdrawing groups > > H3C H > OH H3C C H2 H3C O O O O O CH3 > H3C Ph H3C 1.5. deactivated by electron donating groups, bulky groups, resonance 1.6. alkyl groups stabilize, and sterically inhibit attack, sp2 to sp3 (see hydration) 2. Hydration – water addition 2.1. readily occurs for formaldehyde (reactive carbonyl) but not acetone 2.2. steric and electronic effect NH2 Chem 43-6311, ch8-physical-organic-sykes-co-addition.docx 2016January17 page 2 2.3. hydration unfavorable for most ketones 2.4. hydration is reversible, 18O slow at pH 7, fast with trace acid or base 2.5. occurs in acid or base condition. 2.6. RDS is water addition. 2.7. GA, GB, SA and SB catalysis. 2.8. What is mechanism with base-catalyzed water addition? H3O+ O O H O H O H + H3O H3C H3C CH3 H2O CH3 H3C H3C CH3 OH2 CH3 OH H2O 3. Alcohol addition is reversible as well: acetal and ketal formation 3.1. acetals from aldehydes, ketals from ketones 3.2. formation of hemiacetal fast when acid or base catalyzed even if not favorable 3.2.1. hemiacetal is half alcohol, half ether from aldehyde, addition half done 3.2.2. mechanism just like hydration 3.3. protonation of OH leads to dehydration and to acetal 3.4. geminal oxygen assists loss of water by concerted bond making with bond breaking H+ O O H O H H O + H2OR H3C H3C H H3C H OR H OR H3C H H OR HOR HO H H + RO H3C RO H OR H3C H HO H OR H3C H + H3C HOR HO H OR H3C H O R H H OR 3.5. OH is poor leaving group, WHY? protonate first 3.6. note interchange between 3 sp2 and 4 sp3 orbitals, preserves octet 3.7. acid or base conditions forms hemiacetal, only acid forms the acetal. Why? HOR Chem 43-6311, ch8-physical-organic-sykes-co-addition.docx 2016January17 page 3 3.8. drive reaction to completion with water or alcohol 3.9. acetal is base stable, requires proton for loss of OR group 3.9.1. ketals normally only form with diols O O O H+ + HOCH2CH2OH H2 C CH2 O O H + H2O H 3.10. acetal and ketal formation good for protecting carbonyl from nucleophiles and strong bases 3.11. thioacetals and thioketals also form, not as readily reversible O + 2RSH H3C R H+ S R S H3C CH3 + H2O CH3 4. cyanohydrin 4.1. quantitative for aldehydes and ketones but not aromatic ketones: 4.2. HCN plus catalytic amount of base. show mechanism? 4.3. CN attack rate determining, rate = k[R2CO][CN-] 5. HCl addition 5.1. equilibrium poor in water because Cl- is good leaving group 5.2. addition works in alcohol where ether is stable, why? O + HCl H H CH3OH H3CO H Cl + H2O H 6. metal hydrides 6.1. aldehydes and ketone have single H- addition Chem 43-6311, ch8-physical-organic-sykes-co-addition.docx R R R O R H R H R O R AlH3 page 4 R O AlH3 2016January17 H R O AlH3 R Al H+ OH R H H 4 O R 6.2. esters have two H- addition, loss of OR has assistance from geminal oxygen and AlX3? 6.3. LiAlH4 reacts with aldehydes, ketones, esters, carboxylic acids and amides 6.4. Cannot use protic solvent? 6.5. NaBH4, reacts with aldehyde and ketones 6.6. selectively reduce ketone in presence of amide? Amide in presence of ketone? 7. Meerwein-Pondorf – carbon to carbon H transfer O i Pr O OPri Me Me Al OPri R R O OPri O Al H O R Me Me OPri R O + R H HO H Al H O R OPri R OPri R 7.1. metal alkoxide transfer H 7.2. 6-member cyclic transition state 7.3. Al is important in bringing together alkoxide and carbonyl 7.4. equilibrium determined by reactivity of carbonyl 7.5. driven by removal of propanone by distillation 8. Cannizzaro Reaction 8.1. disproportionation, two aldehydes, one oxidized, the other reduced R R Chem 43-6311, ch8-physical-organic-sykes-co-addition.docx Na Ph H O O Ph H Ph Ph H OH Ph Na O O H Ph O OH Ph H OH OH page 5 Na O O 2016January17 H H 8.2. Rate = k[PhCHO]2[HO-] 8.3. Hydride transfer assisted by geminal oxygen 8.4. does not work with ketones, alkyl does not migrate 9. amino group addition 9.1. acid catalyzed, but not too much, Why? O - O + RNH2 + N H2R B HO + NHR BH + H2 O NHR two steps + H2O + N HR B NR NHR + 9.2. low pH (RDS changes with pH) 9.2.1. water elimination is fast (why?) 9.2.2. amino group is protonated and amino addition is rate limiting 9.3. high pH 9.3.1. water elimination is slow (why?) and rate limiting 9.3.2. amine addition is faster 9.4. imine is more stable than enamine but tends to polymerize 9.5. secondary amines can only form enamines (why?) 9.6. enamine is formed like an enol 9.7. powerful nucleophiles when R = OH, H, alkyl, NH2, NHCONH2, NHPh 9.7.1. i.e. H2NOH, NH3, H2NNH2, etc. 10. Grignard addition Br R' Mg R' R R Br O Mg Br R' Mg Mg R' R' R R Br O Mg Br R' O R Mg Br R R C CH2 R H Mg Br R O R 10.1. chelation by Mg important, impedes acid base reaction 10.2. acid base reactions compete for carbonyl with -H 10.3. reaction with esters? R R C CH2 H R Mg Br R O Chem 43-6311, ch8-physical-organic-sykes-co-addition.docx R R2C R' O page 6 H H R2C 2016January17 Mg Br R' R O Mg Br 10.4. RLi 10.4.1. tend not to undergo acid base reaction, or hydride transfer 10.4.2. prefer 1,2 over 1,4 addition 10.5. R2Cd react with ketones/aldehydes but not esters 11. acetylide addition Na HC CH NaNH2 O O HC C Ph HC C H Na neutralize H Ph 12. aldol condensation 12.1. base catalyzed – enolate formation O H O NaOH CH3 H H2O O Na CH2 O H CH3 H Na NaOH O C H2 H2O CH3 H H O OH C H2 CH3 H 12.1.1. carbonyl activates -CH, stabilized anion 12.1.2. equilibrium favorable for aldehydes 12.1.3. not favorable for ketones 12.2. acid catalyzed – enol formation add proton 12.2.1. favorable for aldehydes and ketones 12.2.2. tertiary alcohol products dehydrate, easy formation of tertiary carbocation 12.3. crossed aldol Chem 43-6311, ch8-physical-organic-sykes-co-addition.docx 2016January17 page 7 12.3.1. mixed aldehydes gives four possible products if both aldehydes have -H 12.3.2. synthetically useful if one does not have -H O Ph H3C H CH3 O OH H+ O + Ph H C H2 H+ CH3 Ph O H C C H CH3 13. Claisen Condensation add a lone pair HOEt O EtO NaOEt CH3 O EtO Na O O CH2 EtO CH3 EtO Na O C H2 O CH3 O C H2 EtO OEt O EtO 13.1. unfavorable leaving group assisted by geminal oxygen 13.2. pKa of -keto ester? 13.3. equilibrium favors -keto enolate 13.4. neutralize to obtain product 14. Dieckmann - intramolecular Claisen condensation (in class) 15. Benzoin condensation 15.1. Aromatic aldehydes used to avoid aldol condensation 15.2. start with cyanohydrin formation 15.3. Rate = k[ArCHO]2[CN-], rate determining step? nucleophilic catalysis 16. Benzylic acid rearrangement CH3 NaOEt O C H CH3 HOEt Chem 43-6311, ch8-physical-organic-sykes-co-addition.docx 2016January17 page 8 16.1. migration of Ph to electron deficient atom (carbon) 16.2. similar to rearrangement of carbon cation 16.3. in PhCOCHO, H instead of Ph migrates 17. Wittig reaction PPh3 + CH2Br PPh3 H2C HC - Br Ph Ph BuLi Ph3 P PPh3 + Ph Ph O HC O Ph3P O CH Ph 17.1. Phosphorus like amine, good nucleophile, not as good base (poor overlap) 17.2. Phosphorus is polarizable, lone pair deformed by electrophile 17.3. formation of strong P=O bond drives reaction 17.4. does not react with esters or unconjugated C=C 18. Addition/elimination of acid derivatives: X = direct heteroatom attached: halogen, S, O, N O O O X X R R X Y Y R Y 18.1. trigonal-tetrahedral interchange, oxygen lone-pair assisted dissociation 18.2. concerted SN2 never observed 19. AKA acyl transfer reactions (for example, from X to Y) O O > R Cl R O O O R > R O > OR' R NH2 19.1. base “catalyzed” hydrolysis of esters follows this mechanism O O O O + H3C 18 H3C OR' 18 OR' OH H3C 18 OH + OR' H3C H18OR' O OH 19.2. no attack on R’, no label in carboxylate: Carbonyl 18O shows up in water. How? 19.3. H* = 112 kJ mol-1, S* = -109 J K-1 mol-1 19.4. OH-, OR-, RNH2 attack ester carbonyl without acid catalysis 20. acid catalyzed hydrolysis: Chem 43-6311, ch8-physical-organic-sykes-co-addition.docx H3O O H3C 18 O + H3C OR' H O H2O 18 OR' H3C O 18 H3C OR' H3C OH 18O H3O+ H3C OH + H3O+ OR' OH O + H18OR' page 9 H 18 H2O OH + H18OR' 20.1. H OH2 O 2016January17 H + H2O H3C H2O 18 OR' OH H in carbonyl, 30 min recover all starting material, missing some 18O, is in the water? 20.2. H* = 75 kJ mol-1, S* = -105 J K-1 mol-1 20.3. normally O-acyl not O-ether cleavage 20.4. If R’ makes good carbon cation (tert-butyl or benzyl) carboyxlate leaves and ether oxygen cleaves O H3C H3O 18 O CH2Ph H3C OH OH 18 O CH2Ph -H + CH2Ph H3C 18 O H2OCH2Ph H2O 20.5. For t-butyl ester: H* = 112 kJ mol-1, S* = 55 J K-1 mol-1 20.6. if acyl group is bulky, acylium is formed (strongly ionizing solvent required?) O O 18 OEt 18 OEt O OH2 H H 20.7. acid esterification, same mechanism and restrictions 20.8. acid hydrolysis activation parameters indicate two different mechanisms HOCH2Ph Chem 43-6311, ch8-physical-organic-sykes-co-addition.docx 2016January17 page 10