Chapter 10 Organic Reaction Mechanisms, Part 1: Reactions Involving Additions and/or Eliminations Addition reactions 10.2 Hydration of carbonyl structures RO OR R R acetal 1 10.2.1 Acid-base catalysis See section 9.3 2 10.2.2 The thermodynamics of the formation of geminal diols and hemiacetals 1. Ketones and aryl aldehydes: less than unity, favoring the carbonyl group 2. Aliphatic aldehydes, carbonyl structures with EWG, and carbonyls in strained rings: greater than unity 3. Aldehydes are more hydrated than ketones because steric congestion in the geminal diol is less. 4. EWG destabilize the already electrophilic carbonyl, leading to greater hydration. 5. Strained rings such as cyclobutanone prefer the sp3 hybridization of a hemiacetal carbon over the sp2 hybridization of a carbonyl carbon. -> smaller bond angle of an sp3 center3 better matches the bond angles in small rings. pyranose 0.003% 2-pyridone 4 10.3 Electrophilic addition of water to alkenes and alkynes: hydration No scrambling of deuteriums -> the first step is not reversible General acid catalysis: all forms of acid in the medium are reactive, and the protonation is rds 5 10.3.3 Regiochemistry H H more stable; less activation energy less stable product EDG: increase hydration rates EWG (Cl or CN): retard hydration rates enamine vinyl ether 6 involvement of a localized carbenium ion on the more substituted carbon 10.3.4 Alkyne hydration very similar to alkene hydrations 7 10.4 Electrophilic addition of hydrogen halides to alkenes and alkynes Two cases A rearrangement The product ratio depends on neither [HCl] nor [added Cl-]. If Cl- and HOAc compete for addition to a transient carbenium ion, one would expect increasing chloride concentrations to divert the intermediate to the formation of alkyl chloride products, but this is not seen. Cl- diffusion is slower than rearrangement -> added Cl- does not affect the product ratio. 8 B The product ratio from the addition of HCl to cyclohexene in HOAc does depend on [added Cl-]. - Increase in added Cl ->this product Why? Consider stereochemistry of this reaction. Second order reaction 9 Added Cl- increases in this product ratio. 10 10.4.3 Addition to alkynes Cl+ vinyl carbocation major product -> lower stability than trigonal sp2 carbenium ions -> addition of HX to alkynes is slower than with alkenes Because of the lower stability of vinyl cations relative to alkyl carbenium ions, concerted reactions occur. Anti addition product; predominantly 11 10.5 Electrophilic addition of halogens to alkenes halonium ions anti addition F2; so exothermic, explosive Cl2; exothermic by 44 kcal/mol Br2; exothermic by 29 kcal/mol I2; near thermoneutral or endothermic -> readily reversible 12 anti addition 10.5.3 Other evidence supporting a σ complex 1. kinetics hydration rates If a non-bridging carbenium ion were formed, one would expect substituent effects similar to that seen for alkene hydration. -> but this is not the case. -> σ complex formation 13 2. Kinetic isotope effects kH/kD = 0.53 (large inverse KIE -> significant rehybridization of both alkene carbons in rds) sp2 -> sp3 3. Addition of other nucleophiles other than bromide Br Br δ+ δ+ MeOH 4. Isolation of bromonium ions Steric hindrance impedes nucleophilic attack 14 anti syn anti syn Carbenium ions can be stabilized by resonance 15 the complex is formed rapidly prior to rds. 10.5.4 Mechanistic variants at low concentrations of bromine or in water and alcohol In solvents of lower polarity, even acetic acid, the reaction is second order in bromine. F2 addition -> syn addition Carbocation rapidly combines with F- before dissociation of the ion pair. 16 10.5.5 Addition to alkynes Alkyl-substituted alkynes show anti addition products with bromine, again supporting a brominium ion intermediate. However, alkynes generally react 103 to 107 times slower than alkenes. ring strain and positive charge on sp2 orbital Aryl alkynes ρ = -5.17 (large negative value) -> EDG 반응속도-> vinyl 증가 cation intermediate 17 10.6 Hydroboration THF diborane borane H2O2, NaOH OH H syn addition Addition of boron to a less hindered carbon Addition; anti-Markovnikov product 18 10.7 Epoxidation mCPBA (m-chloroperbenzoic acid) syn addition The more electron rich the double bond, the faster it will react with the peracid. Sterics are the primary factor directing the epoxidation stereochemistry. The least hindered face of a double bond is predominantly epoxidized. carbocation charater가크다; sp2 -> sp2 Almost no secondary KIE sp2 -> sp3 A relatively large inverse KIE 19 10.8 Nucleophilic additions to carbonyl compounds Cyanohydrin formation cyanohydrin Aldehydes are more reactive than ketones because steric congestion in the cyanohydrin is less. CN- is a very good nucleophile -> protonation is not required prior to or at rds rate = k[CN-][C=O] -> no dependence on acid 20 Grignard addition Extremely fast even at -85 oC two electron nucleophile For some carbonyl compounds electron transfer mechanism: carbonyl structures that lead to stabilized ketyl anions will favor this mechanism, such as conjugate enones, phenyl ketones, and phenyl aldehydes. -> evidence; hydrogen abstraction products (B 첫번째) or radical coupling products (B 두번째) are formed. 21 Lithium aluminum hydride reduction A lithium-specific cryptand A lithium cation is involved in the reaction. 22 10.8.6 Conformational effects in additions to carbonyl compounds The addition of nucleophiles to carbonyl compounds is often found to occur faster with six-membered ring cyclic ketones than with acyclic ketones or cyclopentanones. o Why? The dihedral angle between the Heq and the carbonyl oxygen is only 4 . This near eclipsing interaction produces a conformational strain of around 4 kcal/mol that raises the ground state energy of cyclohexanones relative to acyclic systems. Upon nucleophilic attack, this near eclipsing interaction is relieved, but we introduce a 1,3-diaxial interaction with an oxygen anion. However, the diaxial interaction is estimated to be only 0.7 kcal/mol destabilizing (the A value for an OH), and so the net effect is that a significant amount of strain has been released in this reaction. Release of eclipsing interaction (4 kcal/mol) but increase in 1,3 diaxial interaction (0.7 kcal/mol) -> a significant amount of strain has been released near eclipsing interaction 23 10.8.7 Stereochemistry of nucleophilic additions Rs O Rs OH Rs OH Rm Rm R Nu + m R Rl R Rl R Rl Nu major minor S기 쪽으로 공격 Cram’s model S기 쪽으로 공격 Karabatsos’ model Felkin-Ahn model 24 Cram’s model Felkin-Ahn model 25 Cyclic carbonyl structures LAH reduction; trans -> major Due to these strains, H- attacks more sterically hindered face of the ketone 1. 3번위치에H 이외의 치환기가 있으면 hydride 반응시 cis가 major 2. Larger Nu -> cis product as a major due to steric hindrance 26 Meerwein-Pondorrf-Verley reduction (the reverse reaction is called the Oppennauer ocidation) equilibrium More stable less stable 27 FAD: one electron and two electron reactions NADH(P): two electron (or hydride) reactions 28 10.9 Nucleophilic additions to alkenes Much less favorable than a carbonyl. But when strongly EWG are placed on an alkene, nucleophilic addition can occur. Michael addition (1,4 addition) 29 10.9.4 Baldwin’s rule These rules allow chemists to predict the ease of ring closure reactions. Three factors are considered: 1. ring size, 2. hybridization of the carbon undergoing attack, 3. whether the bond undergoing attack will be endocyclic or exocyclic to the forming ring in the product. The ease of intramolecular formation of a particular ring size generally followed the trend, 5> 6 > 3 > 7 > 4 > 8-10. This holds for intramolecular nucleophilic, as well as radical and cationic ring closures. sp = digonal, sp2 = trigonal, sp3 = tetragonal 30 Nu Nu Nu trigonal large distortion -> unfavorable digonal Nu Nu favorable 31 10.11 Carbene additions and insertions Triplet states should be preferred at the linear geometry (Hund’s rule), and indeed it is. H-C-H angle becomes small enough -> singlet states Angle is 136o for the triplet and 105o for the singlet. While simple carbenes have a triplet ground state, approapriate substituents can reverse this preference. -> carbenes with lone-pair donating substituents such as N, O, and halogens can have singlet ground states because of such an interactions 32 Singlet carbene addition to alkenes Triplet carbene addition to alkenes Singlet carbene insertion into a C-H bond Triplet carbene insertion goes via radical abstraction followed by recombination 33 Carbene generation Thermal decomposition of diazoalkanes Base-induced eleimination of nitrosourea N-nitrosourea Base-induced eleimination of tosylhydrazone Decomposition of diazirine Base-induced alpha eleimination of haloform All the thermal protocols described above initially form singlet carbenes, as do the photolysis of 34 diazo and diazirine compounds. The Simmons-Smith reagent (ICH2ZnI) also act as a carbene source. However, the reaction between CH2I2 and Zn does not generate a full-fledged free carbene, but instead a carbenoid. Carbenoid is a carbene that is stabilized by complexation to a metal. 35 Mechanism Singlet carbenes give 100% stereospecific reactions (syn addition). Triplet carbenes give mixtures. spin flip Triplet carbenes triplet biradical spin flip - Stereochemistry of the alkene is typically not completely lost in the product, which indicates that the spin inversion and bond rotation rates must be comparable. - The more electron rich the alkene, the faster the carbene addition. - The dialkylcarbenes (more unstable)