Structure and Reactivity

Transcription

1 Structure and eactivity Fall Semester 2007 Summary Prof. Jérôme Waser C jerome.waser@epfl.ch Assistant: Simone onazzi C simone.bonazzi@epfl.ch Structure and eactivity 2007, Summary page 1

2 Structure and eactivity: Summary 1. Conformational Analysis (Energy Values in Kcal/mol, M = dium, = arge) 1.1 Alkanes utane Sägebock C 3 3 C 3 C 1 C C ewman Gauche Interaction C 3 C 3 3 C 3 C 3 C C 3 3 C C 3 1 elative Energy C C 3 C staggered antiperiplanar eclipsed anticlinal staggered synclinal gauche conformer eclipsed synperiplanar Special Interaction for Pentane: 1.2 Alkenes: Allylic Strain 5.5 Double Gauche Pentane or Syn Pentane Interaction Allylic A 1,2 Strain 1 3 M 2 Allylic A 1,3 Strain M A 1,3 Minimized: - in free room to D -towards M 3 A 1,2 Minimized: - in free room to D -towards 1 Favored for 2 bigger 1 Favored for 1 bigger 2 -If 1 and 2 are of similar size, A 1,3 is more important. - 3 is usually less important for selectivity. Structure and eactivity 2007, Summary page 2

3 1.3 Cyclohexane chair E a =10kcal/mol chair boat E rel = 6.6 kcal/mol.... half chair twist boat half chair E rel =10kcal/mol E rel = 5.3 kcal/mol E rel =10kcal/mol C 3 C 2 C 3 C(C 3 ) 2 C(C 3 ) 3 C 2 C 2 Et C C C- C = C 2 C 6 5 Si(C 3 ) 3 Sn(C 3 ) 3 2 CC 3 C 3 3 F r I A value axial 2 gauche interactions (also called 1,3-diaxial interactions) equatorial Avalue()=-ΔG (axial-equatorial)!!! A value are exact only for monosubstituted cyclohexanes!!! Important Exception: Anomeric Effect n σ C- n A value: -0.6! Axial is favored n σ C- σ C- σ C- Anomeric Effect: In the axial position, a better stabilization with the more electronegative σ C- is possible. Structure and eactivity 2007, Summary page 3

4 1.4 ther Important Stereoelectronic Effects Gauche Effect σ C- σ C- σ C- σ C- More Stable 2goodσ C- σ C- interactions Enolate Formation 1 1 Π* C= σ C- 1 ydrogen is acidic only to C=! Microscopic eversibility: Protonation from Enolate is to C=C! 2. C=C Functionalization 2.1 ydroboration ydroboration with 3 : Minimize strongest Allylic strain, 3 comes opposite from 3 M M M 2 3 M 2 A 1,3 Minimized 3 M M 3 2 M M A 1,2 Minimized egioselectivity: goes to more stabilized carbocation, because the mechanism is asynchronous: Partial positive charge δ + 2 tertiary carbocation > secondary carbocation > primary carbocation Structure and eactivity 2007, Summary page 4

5 ydroboration with bulky boron reagents: Minimize reagent-substrate interactions 1 3 M 2.2 Epoxidation 2 M eagent control is important! Directed Epoxidation with m-cpa A 1,2 not minimized 1 M M 3 2 M 1 A 1,2 minimized but strong steric interaction with reagent! m-cpa 1 directs m-cpa A 1,3 minimized Prediction easy for cyclic substrates: m-cpa Directed reactions often allows for good selectivity in organic chemistry! Sharpless Asymmetric Epoxidation Allylic binds to Ti: directed reaction Substitution at 4 is not tolerated Important: - t u does not react until bound to Ti Catalysis is possible - Face of attack of the peroxide is determined by the chiral diester ligand, not the conformation of the substrate very good reagent control Structure and eactivity 2007, Summary page 5

6 2.3. Fürst-Plattner ule u thermodynamically more stable r 2 u r r u twist boat, high energy u r also for epoxide opening u directly to chair favored product The thermodynamically more stable product is not observed, because an unvaforable twist-boat intermediate has to be formed. 3. Addition to Carbonyl Compounds 3.1. Felkin-Ahn Model M 1 u 1 ürgi-dunitz Trajectory M 1 M - is to C= - u comes along the ürgi-dunitz trajectory (109 C to C=) - Minimize u-substrate interaction Smallest Substituent on ürgi-dunitz trajectory (ere ) u u M 1 Polar Felkin-Ahn ule Electron-deficient groups behave as n u u σ* C- M 1 Favorable Interaction n u to σ* C- =,F,,r,I, Addition to Carbonyl Compounds ot Following the Felkin Ahn Model Chelate Control M 1 1 M tal M M u 1 1 M M u M M 1 u - tal forces two donors in plane through chelation - u comes towards smallest substituent () Structure and eactivity 2007, Summary page 6

7 Factors favoring chelation - group sterically not hindered: good: =, n, C 2 (MM), nc 2 (M) bad: = t u, Si 3,Si t 2 u (TDMS or TS), Si 3 (TIPS) - non-coordinating solvents: Toluene, C 2 2 >> Et 2 >TF>>DMF,Et, 2 - Strong ewis Acid, with more than one coordination site available ad: a +,K + (too weak ewis Acid), F 3 (only 1 coordination site), i Good: Mg 2,Zn 2,i,Ti 4,Sn 4,Sn 2,n 3,Al 3,... Importance of anion : If is not too tightly bond to the metal, it can dissociate generating a new free coordination site. F -, - generally don't dissociate, - and Ac - can dissociate and r -,I -,Tf - often dissociate easily. For example F 3 is not a chelating agent, but u 2 Tf is a chelating agent Directed eduction 1 Ac Ac a(ac) Ac Ac - Chair transition state - All groups equatorial 1 1 Antoduct chelate conditions give syn! Sodium trisacetoxy borohydride is a very weak reducing reagent nly intramolecular reduction is possible eagents inding to Carbonyl During Addition orane eduction M 1 2 M 1 2 M is to C= - 2 bind to during reduction - Minimize 2 -Substrate interaction Smallest Substituent towards 2 () M ther important examples where Felkin-Ahn models does not apply: Allylation, Aldol eactions via Chair Transitions States Structure and eactivity 2007, Summary page 7

8 4. Allylation Allylation C Crotylation C C - 6-membered, chair transition state - Substituent in equatorial position - Transfer from double bond geometry to stereochemistry ( E to anti, Z to cis) Chiral eagents For Allylation eactions C i 2 Pr C i 2 Pr oush eagent C C 2 C 2 Minimize n -n repulsion and dipole interaction Ester group in axial position further away interaction less important C 2 (-)-Ipc 2-allyl rown eagent Structure and eactivity 2007, Summary page 8

9 5. Aldol eactions 5.1 Enolate Generation With DA For big (C 3, 2 ) 2 DA i / interaction minimized i i Z (Cis) Enolate For small (, ) i / interaction minimized i i E (trans) Enolate exception for esters: Adding MPA leads to Z (Cis) Enolate 2 P 2 2 MPA: good ligand for lithium Cyclic transition state is partially disrupted Deprotonation of Imides with u 2 Tf and Et 3 (soft enolization) u 2 Tf Et Tf u 2 u Tf u Et 3 Et 3 u u - Et + 3 Tf - Cis Enolate only Deprotonation of Ketones 1 9--Tf Et 2 1 Minimize 1 / Tf Et 2 1 Very strong A 1,3 with Imides! Tf Et 2 - Et 2 + Tf - Cy 2 Cy Et 1 Cy 1 - Et Tf - Cy 2 Cy Cy 1 Et 3 * Minimize Cy 2 / Et 3 Trans Enolate *The complete switch of selectivity is not well understood, some authors proposed an extra -hydrogen interaction 1 Cis Enolate Structure and eactivity 2007, Summary page 9

10 5.2 Zimmermann-Traxler Transition State M 2 Cis Enolate 1 M 2 trans Enolate 1 1 M M 1 1 M - Chair transition state (Zimmerman-Traxler) - group of aldehyde equatorial - Geometry of double bond transfered to stereocenter: cis to syn, trans to anti 5.3 Evans Auxiliary M 1 syn product 1 anti product Evans Syn Aldol: 2 Tf 1 C 1 c Et 3 i up to 500 : 1 Pr Transition States - Chair Transition State - Minimized Dipoles - Aldehyde comes opposite from 1 1 ewman view from the left Important: In order to activate the aldehyde for addition, has to bind to the aldehyde. As has only two free binding sites, the oxazolidinone carbonyl is now free and rotates to minimize dipole interactions. Crimmins Syn Aldol Ti 4 base Ti 1 C 1 c n Transition States n 1 Ti - Chair Transition State - All Carbonyl bound to Ti - Aldehyde comes opposite from n n Ti 1 ewman view from the back Structure and eactivity 2007, Summary page 10

11 Anti aldol with external ewis Acid 1 2 Tf Et Ketone (Paterson) Aldol 1 C Et 2 Al 1 -Freetransitionstate(nochair) - chelates the auxiliary - Minimized dipoles and steric: carbonyl antiperiplanar to enolate - Aldehyde comes opposite from - 1 group away from auxiliary c 1 AlEt 2 ewman view from the back M 2 1C 1 Minimized steric M 1 M 1 M M 2 1C M 1 M 1 1 M - Chair transition state Minimized A 1,3-1 group of aldehyde equatorial - position of chiral group: minimize steric interaction with 2 for cis enolate, aldehyde comes towards M,not, minimize A 1,3 with of enolate for trans enolate, M and not towards 2,aldehydecomestowards 5.5 Proline Catalyzed Aldol 2 C 2 2 C 2 96% ee Structure and eactivity 2007, Summary page 11

12 6. earrangements 6.1 Cationic earrangements electrons - 3 centres transition state ame eactions: Wagner erwein, Pinacol, semi-pinacol, Prins-Pinacol. The group which stabilizes the best the cation is migrating Prins-Pinacol: Ph Sn 4 Ph 4 Sn Ph Prins Ph 4 Sn Ph 4 Sn Pinacol 6.2 Carbene and itrene earrangements carbene important special case: 3 C ketene 3 ame eactions: Fritsch-uttenberg-Wiechell, Arndt-Einstert, Wolff. nitrene important special case: C isocyanate ame eactions: Curtius, ofmann, ossen, Schmidt 6.3 [3,3] Sigmatropic earrangements Y Y 3 - Chair transition state (with rare exceptions) - groups at SP 3 centers equatorial - Transfer of double bond geometry to stereocenter and stereocenter to double bond geometry 1 2 Y ame eactions: Cope ( = C), xy-cope ( = C, 3 = ), Anionic xy-cope ( = C, 3 = -), aisen ( = ), Johnson-aisen ( =, Y = ), Ireland-aisen ( =, Y = i, Si 3 ) Structure and eactivity 2007, Summary page 12

13 7. Umpolung 7.1 Stoichiometric Umpolung eagents Acyl anion equivalents: = S S Dithiane C Cyanide itronate Electrophile α to carbonyl: = Catalytic Umpolung The enzoin Condensation The Stetter eaction cyanide cat. carbene cat. ' carbene cat. ' chanism for the carbene - catalyzed benzoin condensation: ' S Proton Transfer ' S reslow Intermediate ' S base ' S ' S Proton Transfer ' S Structure and eactivity 2007, Summary page 13

14 8. eactions Involving - and - onds 8.1 ydrazones Wolff-Kishner eduction ther reactions with hydrazones derived from hydrazine: Wharton rearrangement, arton halogenation 2 eactions of Tosylhydrazones Tos Tos 1) 1 i, TS ial 4 C 3 2) Acid 1 Tos ui 1 Shapiro eaction Umpolung with ydrazones and ximes Tos Ac Eschenmoser Fragmentation ui 1) E + 2) 2, + E Also For xime via 8.3 Polonovski and Pummerer earrangement Polonovski earrangement C 3 1 m-cpa Pummerer earrangement S 1 TFAA C 3 F 3 C CF 3 1 TFAA S 1 CF 3 S S CF C CF 3 2 F 3 C C Structure and eactivity 2007, Summary page 14

15 9. Cross-Coupling and lefin tathesis 9.1 General chanism for Cross Coupling 1 M catalyst 1 catalyst: most often Pd, but also i, Fe 1 Pd 2 xidative eductive Elimination Addition 1 Pd M 1 Pd M Transmetallation Pd 1 M M= 2 : Suzuki M=Sn 3 : Stille M=Zn:egishi M=Mg:Kumada special: 1 -M = 2 Scope: and 1 groups Cu : Sonogashira easy:, 1 = aryl, alkenyl, alkynyl difficult: 1 =alkyl very difficult = alkyl (topic of current research) groups easy:i,r,tf difficult but more interesting:, Tos, 9.2eckCoupling 1 Pd cat. 9.3 lefin tathesis ase-diated eduction 1 base base Pd β- Elimination base Pd 1 1 Pd 2 lefin Insertion Pd Pd 1 xidative Addition 1 igand Exchange catalyst 1 1 n M 1 n M n M Grubbs: stable, functional group tolerant PCy 3 s s u PCy Ph 3 u PCy Ph 3 s = mesitylene s s u Pr 1. Generation 2. Generation oveyda-grubbs 1 1 n M Schrock: more reactive, less stable F 3 C Mo CF 3 CF 3 Ph CF 3 Structure and eactivity 2007, Summary page 15