STEREOELECTRONIC EFFECTS (S.E.) IN ORGANIC CHEMISTRY

Transcription

1 STEEELECTNIC EFFECTS (S.E.) IN GANIC CEMISTY Pierre Deslongchamps (version du 5 février 2010) Cf. pour le livre: 1

2 SECTIN 2 Stereoelectronic Effects (S.E.) and eactivity of Acetals and elated Functions 2

3 3

4 Conformation of acetals 4

5 STEEELECTNIC EFFECTS and xygen Basicity, Bond Length and Preferential Cleavage in Acetal ydrolysis (theory) 5

6 Bürgi-Dunitz Angle of Attack on Carbonyl Group. Evidence from X-ays Diffraction Analysis In molecular containing an amino group and a ketone (119), X-rays shows the N:---C= bond too long for a bond but too short for no bonding. In 120, the C= unit (120 to 121) deviates from coplanarity. In 1,8-disubstituted naphtalene, both substituents are splayed outward. In 122, the C- bond is splayed outward, but the C-N bond leans inward. J.D. Dunitz et al. elv. Chim. Acta 1978, 61,

7 Importance of Lone Pair Electronic Delocalization in Carbonyl Group ( n /π*) in Protein Conformation or Protein-Ligand Interaction Y Y pyramidalization X N Me C Me Me N X C Me distance X S S cis Y F F K trans/cis Evidence from NM, X-rays and computation. trans CNCLUSIN: n-π* electronic delocalization plays an important role in: (1) protein folding (K trans/cis correspond to 0.8 kcal/mol at 25 C); (2) in many protein-ligand interactions.t. AINE et al. J.Am.Chem.Soc. 2009, 131,

8 No Evidence in Favor of Stereoelectronic Control in Acetal ydrolysis in Early Studies In 10 anomeric pairs of alkyl glucopyranosides, the β-anomers were hydrolyzed times faster than the α-anomers. faster than Feather arris Also, ydrolysis of p-nitrophenoxy 127 is p-independent in the p range Spontaneous hydrolysis of 127 is 3.3 times slower than 128. It was first concluded that there was no evidence that acetal cleavage is subject to stereoelectronic control. It was later disclaimed as 128 could hydrolyzed via boat conformer 129. Kirby 8

9 Evidence of Stereoelectronic Control in ydrolysis Came with Conformationally igid Acetal Compounds ydrolysis 131 (0.1 N Cl) is > 3000 faster than 130 Kirby Spontaneous hydrolysis elative rate: 1 ~10,000 Ar C elative rate: 1 ~1.2 x Ar 9

10 ydration of Enol Ether vs lefin elative rate: Kresge-Wiseman elative rate:

11 Evidence of Stereoelectronic Control in Acetal Formation Antiperiplanar Lone Pair ypothesis 11

12 12

13 Strength of the Anomeric Effect as a Function of Leaving Group Y E (X = ) N F -2.0 N F E (X = N 2 ) Energy parameters e, e N for electronic component of anomeric effect due to, N (kcal/mol) F. GEIN and P. DESLNGCAMPS. Can. J. Chem. 70, 604 (1992). F. GEIN. In "The Anomeric Effect and Associated Stereoelectronic Effects". Chap. 11 : Anomeric and everse Anomeric Effect in Acetals and elated Functions. Edited by G..J. Thatcher. ACS Symposium Series 539, Washington, D.C.,

14 elative Energy of TS in the Formation of α and β Glycosides Experimental esults P. DESLNGCAMPS, S. LI, Y.L. DY. rg. Lett. 6, 505 (2004). 14

15 elative ate of Formation of α and β Glycosides from Enol Ether T (h) A alpha beta P. Deslongchamps, S. Li, Y.L. Dory. rg. Lett. 2004, 6,

16 Molecular Modeling of eaction Course in Glycoside Formation or ydrolysis 16

17 Alpha anomer 6-31G* Yves DY 17

18 Beta anomer 6-31G* More stable than boat by 4 Kcal/mol Yves DY Same energy 18

19 ydrolysis of α and β-glycosides. Molecular Modeling of eaction Pathway (F/6.31G*) 2α TS Me Me 2β TS Me 4.58 kcal/mol Me 1α 0.00 Me - Me 1β Me Me 5α TS 6.30 Me 2 2 5β TS 5.09 TS: 2α < 5α + entropy TS: 2α < 2β TS: 2α < 5β TS: 5β < 2β - entropy 6β < 6α 6α 6.58 Me 6β 5.95 Me = (calculation) = (C 2 ) 4 (experimental) 19 P. Deslongchamps, S. Li, Y.L. Dory. rg. Lett. 2004, 6,

20 Formation of α and β Glycosides from Enol Ethers 11E Me TFA benzene + Me 6α (0.6 kcal/mol) 1α Me 11Z Me " " + Me 6β (0 kcal/mol) 1β (100%) Me TFA Me 19 ESUME F EXPEIMENTAL ESULTS + 1α / 1β (80:20) (kinetic) 1α / 1β (68:32) (thermod.) Intermediates 6β is 0.63 kcal/mol lower than 6α 11E 11Z 19 TFA/benzene TFA/benzene 1β (100%) (kinetic) TFA/Me 1α / 1β (80:20) (kinetic) P. Deslongchamps, S. Li, Y.L. Dory. rg. Lett. 2004, 6, α / 1β (68:32) (thermodynamic) 20

21 Formation of Spiroketals 21

22 Molecular Modeling (AM1) of Spiroketal Formation 22

23 Various Cyclization Pathways in Acetal Formation 23

24 Cyclization Versus ydrolysis as a Function as a ing Size 24

25 Cyclization Versus Addition of Methanol as a Function of ing Size 25

26 Molecular Modeling (AM1) of Ketal Formation as a Function of ing Size 26

27 DEFINITINS 3 Factors: (1) Proton Affinity: E (enthalpy) (bond length 1.6 Å) between ketal + + and ketal - + (2) Decompression energy: E (enthalpy) between ketal - + and oxocarbenium ion (3) Entropy: (bond cleavage and ring closure) 27

28 θ Angle = definition at TS π Bond Model = n-σ* TS is not found in ketal (a constraint C- bond length at 1.6 Å is selected) 28

29 elative ates of ydrolysis of a Series of Ketals S. Li, Y.L. DY, P. DESLNGCAMPS. Israel J. of Chem. 2000, 40,

30 elative ate of ydrolysis of 5-, 6- and 7-Membered Aryl Ketals N.B. Proton affinity (basicity) depends on the strength of the anomeric effect 30

31 elative ate of ydrolysis of 5- and 6-Membered Ketals N.B. Proton affinity (basicity) depends on the strength of the anomeric effect 31

32 elative ate of ydrolysis of 5- to 7-Membered and Acyclic Ketals N.B. Proton affinity (basicity) depends on the strength of the anomeric effect 32

33 elative ate of ydrolysis of 7-Membered Ketals N.B. Proton affinity (basicity) depends on the strength of the anomeric effect 33

34 elative ate of ydrolysis of Dimethoxy and Diethoxy Ketals N.B. Proton affinity (basicity) depends on the strength of the anomeric effect 34

35 CNCLUSIN N ALKYL AND AYL KETALS YDLYSIS 35

36 S. Li, P. Deslongchamps. Tetrahedron Lett. 35, 5641 (1994). P. Deslongchamps, Y.L. Dory, S. Li. Tetrahedron 56, 3533 (2000). C.A. Bunton,.. De Wolfe. J. rg. Chem. 30, 1371 (1954). 36

37 ELATIVE STABILITY: xenium Energies (F 6-31G*) C 3 + C 3 C C 3 0 kcal/mol C 3 C 2 C + 3 C 2 C 2 + C C C kcal/mol 19.1 kcal/mol 37

38 elative ates of Acetals of Formaldehyde, Aldehyde, and Ketone ACETALS x x 10 3 reverse of bimolecular processes (entropy) intramol. proc. methoxy less basic than ethoxy 1 x x x 10 7 reverse of intramol. proc. bimolecular processes methoxy ethoxy (2 cleavages) entropy 3.7 x x x x x reverse of intramol. proc. methoxy (2 cleavages) entropy bimolecular processes ethoxy methoxy (2 cleavages) (1 cleavage) ethoxy (2 cleavages) 38

39 Transition State in Glycosides: SN 1 versus SN 2 Mechanism Same Basic Geometry 39

40 SN 1 versus SN 2 in Glycoside Depends on eaction Conditions + SN 1 oxenium Nu + Nu X SN 2 + Nu Nu X N.B. xenium exists in the presence of weak nucleophile. In the presence of water, it does not exist. K.. WEPEL et al. J. rg. Chem. 2009, 74, (eview). 40

41 ydrolysis of Acetals: Gauche versus Eclipsed Conformers and π-bond Model 41

42 Synperiplanar Stereoelectronic Effect and ydrolysis in Acetal 42

43 Acetals with Synperiplanar Lone Pairs: Crystal-Structure-eactivity 1 n x Ar n = 1.32 x = : a marked lengthening of x and shortening of n By comparison with 3: no significant change CNCLUSIN: The anomeric effect due to the synperiplanar n -c* C- overlap in acetal 3 is less efficient than the antiperiplanar one in simple TP acetals 1 in their respective ground state. P. Deslongchamps, P.G. Jones, S. Li, A.J. Kirby, S Kuusela, Y. Ma. J. Chem. Soc., Perkin Trans. 2, 1997,

44 ow About ydrolysis? 1 n x Ar 3 n x Ar In spontaneous hydrolysis, 3 is slightly faster than The ground state of 3 is in a boat, thus containing more energy than 1 which is in a chair form. 3 is thus energetically closer to TS. 2. TS is late resembling the corresponding cyclic oxenium ion in both reactions (the endocyclic oxygen is sp 2 hybridized in both cases). 44

45 ydrolysis of β-glycosides via Anti- and Synperiplanar Pathways chair half-chair TS twist-boat N.B. The syn pathway goes through a half-chair which is higher in energy than the twist-boat. In cyclohexane, half-chair = 10 kcal/mol and twist-boat = 5 kcal/mol. 45

46 elative ate of Acetolysis of Glycopyranosides (Electrostatic Stabilization by Electron Lone Pairs on xocarbenium Ion) Stabilization of oxocarbenium by axial C 4 -X group esults of relative rates: 3 (0.5), 4 (1.6), 5 (0.6), 6 (0.5) (similar) 2 is slightly faster (2.4) 1 is much faster (24) M. Miljkovic, D. Yeagley, P. Deslongchamps, Y.L. Dory. J. rg. Chem. 1997, 62,

47 Acetolysis of α and β-galactosides and Glucosides (Complete Agreement with ab initio Calculation) Me ELATIVE ATE much faster than Me Me Me Me slightly faster than Me Me Me Me N slightly slower than Me N Me Me M. Miljkovic, D. Yeagley, P. Deslongchamps, Y.L. Dory. J. rg. Chem. 1997, 62,

48 eactivity of Cyclic xenium Ac + BF 3 :Et 2 Nu Nu α Nu + β Nu Nu α Nu Nu + β Nu N.B. (1) True with weak nucleophiles. (2) With strong nucleophile, no selectivity due to early transition state (approach the diffusion limit). K.. WEPEL et al. J. rg. Chem. 2009, 74, (eview). 48

49 elative Stability and eactivity of Cyclic xenium in the Presence of Electron-Donating Substituents everse results when is replaced by alkyl group in first two examples (K.. Woerpel). 49

50 Electrostatic Interaction on 4-Substituted Tetrahydropyran xocarbenium Ion explanation K.A. WEPEL et al. J.Am.Chem.Soc. 2003, 125,

51 Electrostatic Interaction on Tetrahydropyran xocarbenium Ion Influence on Chemical eactivity N.B. 3 is stabilized by hyperconjugation from C2- axial? ther explanation next slide K.A. WEPEL, M.T. YANG. J.rg.Chem. 2009, 74,

52 eactivity of C-2 Alkoxy Substituted Tetrahydropyran Cation Bn + Bn + Nu slow Bn slow fast Bn + Nu fast Bn Deslongchamps 52

53 Evidence Against the ole of Neighboring Group Participating via a Bicyclo[2.2.1] Intermediate cis trans trans CNCLUSIN: Even if 14 is more stable, reaction takes place via 12 to give 1,4-cis (4). N.B.: Probably 13 does not exist and the equilibrium is between 12 and 14 (WY?) K.A. WEPEL et al. J.Am.Chem.Soc. 2008, 130,

54 Evidence Against the ole of Neighboring Group Participating via a Bicyclo[2.2.2] Intermediate Intermediate 17 ( = Et) can be isolated at -40 C. Major formation of 1,4-cis product comes from S.E. controlled reaction on oxocarbenium ion 15. K.A. WEPEL et al. J.Am.Chem.Soc. 2008, 130,

55 Electrostatic Interaction on Tetrahydropyran Dioxocarbenium Ion Influence on Conformational Stability NM CALCULATIN * Contrary to TP oxocarbenium ion, dioxocarbenium ion can be isolated (NM, X-rays). K.A. WEPEL, M.T. YANG. J.rg.Chem. 2009, 74,

56 More Calculations on Electrostatic Interaction on Tetrahydropyran Dioxocarbenium Ion and Conformational Stability * Contrary to TP oxocarbenium ion, dioxocarbenium ion can be isolated (NM, X-rays). K.A. WEPEL, M.T. YANG. J.rg.Chem. 2009, 74,

57 elative Nucleophilicity of the Group at C 4 in Glycosides (emote Consequence of the endo-anomeric Effect) When phenyl tri--benzyl-1-thio-β-dgalactopyranosiduronic acid esters were coupled with a 1/1 mixture of α and β 2,3 di--protected D-galactopyranosiduronic acid esters, the β-anomer proved to be more reactive. at C 4 in 7β is more basic Doutheau, Deslongchamps et al. rg. Lett. 2000, 2,

58 Stereoelectronic versus Steric in Prins Cyclization eactions! C. + In Tf 3, TMSBr C 2 Cl 2, 0 C Y Y = TMS or Me Br Y MeC 90:10 (trans/cis) T.-P. L et al. rg. Lett. 2009, 11,