Small Ring Conformational Analysis in Chemistry, Lecture notes of Chemistry

Download Small Ring Conformational Analysis in Chemistry and more Lecture notes Chemistry in PDF only on Docsity! E. Kwan Small Ring Conformational Analysis Chem 106 Small Ring Conformational Analysis | Key Questions: Eugene E. Kwan : (1) Why are cyclopropanes unusually stable? What is the nature of their bonding? Nuc ' JN @ | (2) What are the conformations of cyclohexane and o cyclohexene? OBn me: LiAID, 2 : (3) Why are the reactions of substituted five- and six- membered oxocarbenium ions diastereoselective? OMe SnBr, Brito + Zs 74 ? OMe PhMe 55%, 95/5 dr Scope of Lecture cyclopropanes and : geminal hyperconjugation ' small ring cyclobutane conformational analysis types of strain . . cyclopentane cylic oxocarbenium OMe ions cyclohexane and its Bno: + ZX TMS SnBra 2 unsaturated derivatives OMe PhMe 85%, 20/80 dr Helpful References 1. Weinhold, F.; Landis, C. Valency and Bonding: A Natural Bond Orbital Perspective 2005, Cambridge, Cambridge University Press. | thank Professor David A. Evans (Harvard) for helpful discussions and the use of some material in the preparation of this lecture. Many of the stereochemical 2. Eliel, E.L.; Wilen; S.H. Basic Organic Stereochemistry analyses here are taken from Chem 206. 2001, New York, John Wiley & Sons, Inc. 3. Electrostatic Interactions in Cations... Smith, D.M.; Woerpel, K.A. Org. Biomol. Chem. 2006, 4, 1195-1201. discussions and feedback in the preparation of this lecture. ' || thank Professor Keith Woerpel (UC Irvine) for helpful lecture notes edited by Richard Liu  E. Kwan Small Ring Conformational Analysis Chem 106 Here is some terminology: (1) What preferentially stabilizes cyclopropane? Strain in Cyclic Systems ‘ Here are some estimates of the strain based on "homodesmotic Strain is a measure of how destabilized one thing is over ‘ reactions" (agrees with experiments for carbon skeletons): another. For example, in the series of cycloalkanes that we theoretical strain will discuss in this lecture, energy (kcal/mol) A QO C) ‘ cyclopropane (C3Hg) 26.8 one might measure their heats of combustion, and call ‘ cyclobutane (C4Hg) 25.7 cyclohexane "strain free," and then talk about how much extra: | . heat of combustion per atom comes from the smaller rings. So: silacyclopropane (Si3Hg) 34.9 strain energy is arbitrary in that it depends on how you define it, ‘ . . but is a useful concept nonetheless. : __ Silacyclobutane (Si4Hg) 15.2 (2) What is the hybridization in these systems? What do torsional strain (Pitzer): involves a strained dihedral angle the orbitals look like? (e.g., 1,2-eclipsing interactions) angle strain (Baeyer): when a bond angle deviates from (3) What is different about the silicon analogs? an expected value (e.g., cyclopropane vs. methane) A key factor that is somewhat unique to three-membered rings is geminal hyperconjugation: steric strain (van der Waals): when the electrons in two groups ® get so close that they have to D D vicinal develop more nodal character to Sl <—_ = interaction maintain mutual orthogonality A & bond strain: when a bond length deviates from some expected geminal equilibrium value yA 5® Se interaction Cyclopropane and Cyclobutane The bond angles in cyclopropane deviate from the tetrahedral angle much less than they do in cyclobutane. Therefore, you may be surprised to learn that cyclopropane and cyclobutane are actually approximately equally strained! Why don't we normally talk about geminal interactions? It turns out that their strength depends a lot on the D-C-A angle. Ina small ring, the angle is small, the overlap is good, and therefore the interaction is strong. E. Kwan, D.A. Evans Small Ring Conformational Analysis Chem 106 Stabilization of Cyclopropyl-Stabilized Carbocations The usual analogy is that cyclopropanes are "olefin-like" and carbocations adjacent to them are stabilized like allyl cations are stabilized. For example, the lowest energy conformation of this cyclopropyl cation is: Me Me © " ZN " H H The barrier to rotation here is 13.7 kcal/mol, which is on par with amide resonance (but is too low for a full z-bond). NBO analysis shows that the skeletal bonds definitely stabilize the ion: occ to n*c: 14.5 kcal/mol Wa ; Conformations of Cyclobutane : Cyclobutane has a slight pucker to it, but the barrier to ' inversion between the two possible puckered forms is very low: oC Just as in cyclohexane, there is a preference for putting substituents in equatorial positions. Conformations of Cyclopentane There are two low energy conformations: eo Me half-chair (C2) very similar in energy envelope (C,) The conversion between these isomers is very rapid and called "pseudorotation." Me H <T* = tN Substituents generally prefer to be in the equatorial ' position, although there is considerable conformational ! flexibility (analyze systems case-by-case). AG° = -0.9 kcal/mol E. Kwan, D.A. Evans Chem 106 Cyclopentanes c w@ 1,2-interactions between C-H bonds is apparently disfavored, as judged by the fact that cyclopentene is about as stable as cyclopentane: 0 ~ ~S > A >~ stability The idea is that introducing sp? centers into the ring cause angle strain, but also remove eclipsing interactions. For example, the NaBH, reduction of cyclopentanone is 23 times slower than the reduction of cyclohexanone because it introduces two new eclipsing interactions: Ht! Wh OH Lo hea Es H IH HH substituents fully staggered reduction develops eclipsing interactions Small Ring Conformational Analysis In general, reactions favor keeping or forming a double bond in 5-membered rings, but favor removing or never forming a double bond in 6-membered rings. Brown JACS 1954 76 47 Cyclohexanes Unlike cyclcopentane, cyclohexane has a well-defined potential energy surface with relatively deep minima. Before describing the landscape in detail, here are some enthalpies (kcal/mol): “& chair (0.0) twist-boat (+5.5) —<\ I ~\\ boat (+6.7) _half-twist (+10.8) half-chair (+ 11.1) The chair and twist-boat forms are energy minima; the others are transition states. The barrier to interconverting cyclo- hexane itself has been estimated at: AG# = 10.2 kcal/mol AH# = 10.7 kcal/mol AS* = 2 cal/mol To understand how the ring flips, we can employ a two- dimensional reaction coordinate diagram (Leventis J Chem | Ed 1997 74813). Interpretation: (1) Structures 1-6 are identical, but displayed from different angles (but would become different if there were any substituents). (2) Primed and unprimed structures are related by a ring flip (e.g., 1 and 1’). (3) Interconversion is possible without passing through a boat TS! (4) The boat is destabilized because of a van der Waals interaction between the carbons rather than the “flagpole” protons. (5) There are substantial deviations in the boat from tetrahedral angles; thus, the hybridizations are not sp3. diagram: see ref on previous page Sauers J Chem Ed 2000 77 332 Two Possible Pathways: (A) chair, half-twist TS, twist intermediate, half twist TS’, chair’ (B) chair, half-twist TS, twist intermediate, boat TS, twist intermediate’, half-twist TS’, chair’ E. Kwan Small Ring Conformational Analysis Chem 106 This is verified by the NBO charges on fert-butylcyclohexanone and its 4-ax-OBn, Me-oxocarbenium congener: cn -0.44 wth, \, 57 w¥ +0.61 sose//bon 40.77 Given that analysis, what is the outcome of this bromination? (Because there is a bromonium ion opening here, the product must be 1,2-anti; the question is, which 1,2-anti?) tBu Br tBu Br tBu Br Oe SO ® “OL “Br Br Bromine comes from the face opposite the tert-butyl group: +0.22 0.65 °} In fact, ab initio calculations predict that placing the OBn Br {Bu Br : axially is favored by 4.6 kcal/mol! (Note that in the cyclohexane TC part itself, the hydrogens are slightly positively charged and the carbons are slightly negatively charged.) . oe . Q: What implications does this have for stereoselectivity? The bromonium ion is opened 1,4 to the tert-butyl group; in age ina OMe general, cyclohexene derivatives are opened chair-axially. OMe OTMS — snBry . ic Si i BnH,c—~ XX + — ~~ Exocyclic Six-Membered Oxocarbenium lons 2 ‘OMe Ap PhMe BnH2C The reactions of charged species are, predictably, strongly 71%, 96/4 dr influenced by electrostatic effects. Even cyclohexanone, OMe which is not formally charged, displays 5 some odd properties: Bro xo + OTMS — SnBr4 R ‘OMe Arr PhMe OBn 86%, 96/4 dr QMe favored ® conformations In both cases, the silylenol ether is a large nucleophile, and 2 : attacks from the equatorial face: One : oF 2 ' ~Me rL—K. “Nuc OBn When polar substituents are in axial positions, they are closer : to the positive charge. Note that while the formal charge is ‘ on oxygen, the actual charge is on carbon. ‘ ‘ Woerpel JOC 2006 77 6851 E. Kwan Small Ring Conformational Analysis Chem 106 ; Analysis: OLOAG pe opt OW Nu Ov Nu ‘ (1) Selectivity depends on Mayr nucleophilicity (N), not size. 3 2 , : ———_ + ‘ mo Nuc not mor ‘ (2) Normal reactivity-selectivity is seen here (see Lecture 4). nucleophile N yield (%) adr ‘ (3) How can product be formed? Z~ SiMe3 1.8 83 8:92 ‘ Sy1 attack on a solvent-separated ion pair OTMS ‘ Nuc A 6.2 87 8:92 ; Af Cy" favored Ph : — —_ . athwa’ ‘ A) Bno™ p y OTMS ‘ OBn a 8.2 88 50:50 1,4-trans product ‘OPh ‘ 4 OTMS : OJ Nu disfavored Me 7 9.0 80 58:42 — 6 NOBn _. OC pathway OMe . . ‘ Nuc SL @® Bno™ Me ‘ 1,4-cis product OTMS ‘ one 10.2 86 60:40 ‘ - the [BF,OAc] counterion is non-coordinating n_Bu - axial OBn is favored over equatorial OBn Woerpel OL 2008 10 4907 . a . - for weak nucleophiles, this is the dominant pathway JOC 2009 74 8039 - as the nucleophile gets more and more nucleophilic, every nucleophile-electrophile encounter results in a reaction, and the reaction becomes diffusion-controlled and therefore unselective ‘. tight ion-pairing has been ruled out (Woerpel, 2005, 7, 1157) E. Kwan Small Ring Conformational Analysis Chem 106 Six-Membered Oxocarbenium lons Interestingly, when TMSOTTH is used instead of BF3:OEt, the selectivity turns over! CY TMSOTE on cy” + : Bno™ Nuc Bno™ Bno”™ nucleophile N yield (%) dr : ZW SiMes 1.8 96 «6:94 OTMS 6.2 95 10:90 Ph oTMS : 8.2 83 71:29 ' ‘OPh : OTMS Me. AA oye 9.0 93 85:15 Me : OTMS 10.2 96 89:11 OnBu - less reactive nucleophiles give trans product; more reactive nucleophiles give cis product - the turnover in selectivity cannot be rationalized by an increase in reaction rate to the diffusion limit Woerpel JOC 2009 74 8039 } Another possibility is an S\y2-type pathway involving either ‘ direct displacement or a contact ion-pair: TIO. Tx ort via direct Sy2 2 7 i “N\A op displacement Nuc Bn OBn 1. Dn. & via Sy2 inversion a A ‘ Of contact ion-par OBn Nuc OBn ‘ (1) Placement of the OBn in an axial position is electrostatically favored. Chair-axial attack occurs as usual. (2) In the contact-ion pair mechanism, the triflate anion shields the top face of the molecule, forcing the reaction to occur through a twist-boat conformation. ‘ (3) Summary: weak nucleophiles, Sy1 pathway; strong nucleophiles, Sy2 pathway possible with triflate anion ‘ Example: What is the outcome of this reaction? O. OAc BF3-OEty Ow Nu Ov Nu + Uae OO UU = TMS : = tBu aN tBu tBu . Nuc- A weak nucleophile, BA 1,3-trans Sy1 reaction via most stable conformer product (1:99 dr)