Chem 206D. A. Evans Matthew D. Shair Monday, September 30, 2002 http://www.courses.fas.harvard.edu/~chem206/ a73 Reading Assignment for week A. Carey & Sundberg: Part A; Chapter 3 Conformational Analysis: Part–3 Chemistry 206 Advanced Organic Chemistry Lecture Number 6 Conformational Analysis-3 a73 Cyclopropane a73 Conformational Analysis of C4 → C8 Rings Three Types of Strain: Prelog Strain: van der Waals interactions Baeyer Strain: bond angle distortion away from the ideal Pitzer Strain: torsional rotation about a sigma bond Baeyer Strain for selected ring sizes size of ring Ht of Combustion(kcal/mol) Total Strain(kcal/mol) Strain per CH2(kcal.mol) "angle strain"deviation from 109°28' 34 56 78 910 1112 1314 15 499.8656.1 793.5944.8 1108.31269.2 1429.61586.8 1743.11893.4 2051.92206.1 2363.5 27.526.3 6.20.1 6.29.7 12.612.4 11.34.1 5.21.9 1.9 9.176.58 1.240.02 0.891.21 1.401.24 1.020.34 0.400.14 0.13 24°44'9°44' 0°44'-5°16' Eliel, E. L., Wilen, S. H. Stereochemistry of Organic Compounds Chapter 11, John Wiley & Sons, 1994. a73 Baeyer "angle strain" is calculated from the deviation of the planar bond angles from the ideal tetrahedral bond angle. a73 Discrepancies between calculated strain/CH2 and the "angle strain" results from puckering to minimize van der Waals or eclipsing torsional strain between vicinal hydrogens. a73 Why is there an increase in strain for medium sized rings even though they also can access puckered conformations free of angle strain? The answer is transannular strain- van der Waals interactions between hydrogens across the ring. Conformational Analysis of Cyclic Systems de Meijere, "Bonding Properties of Cyclopropane & their Chemical Characteristics" Angew Chem. Int. Ed. 1979, 18, 809-826 (handout) Snyder, J. P. JACS, 2000, 122, 544. H H H H H H Nonbonding Ph O H H Me Me C R O Cyclopropane: Bonding, Conformation, Carbonium Ion StabilizationEvans, Kim, Breit Chem 206 Cyclopropane a73 Necessarily planar. a73 Subtituents are therefore eclipsed. a73 Disubstitution prefers to be trans. υ = 3080 cm-1 ? = 120 ° a73 Almost sp2, not sp3 Walsh Model for Strained Rings: a73 Rather than σ and σ* c-c bonds, cyclopropane has sp2 and p-type orbitals instead. side view σ–1 (bonding) σ (antibonding) σ (antibonding) pi (antibonding) pi (bonding) pi (bonding) 3 Carbocation Stabilization via Cyclopropylgroups A rotational barrier of about 13.7 kcal/mol is observed in following example: NMR in super acidsδ(CH 3) = 2.6 and 3.2 ppm R. F. Childs, JACS 1986, 108, 1692 1.464 ? 1.409 ? 1.534 ? 1.541 ? 1.444 ? 1.302 ? 1.222 ? 1.474 ? 1.517 ? 1.478 ? X-ray Structures support this orientation de Meijere, "Bonding Properties of Cyclopropane & their Chemical Characteristics"Angew Chem. Int. Ed. 1979, 18, 809-826 (handout) H H H H H H H H H H H H H H H H H H H H H HHH H H H HH H Me Me H eq ax ax eq ax eq eq ax H H H H H H H H H H X (MM2) (MM2) X X Evans, Kim, Breit Chem 206 Cyclobutane ? = 28 ° a73 Eclipsing torsional strain overrides increased bond angle strain by puckering. a73 Ring barrier to inversion is 1.45 kcal/mol. a73 G = 1 kcal/mol favoring R = Me equatorial a73 1,3 Disubstitution prefers cis diequatorial to trans by 0.58 kcal/mol for di-bromo cmpd. a73 1,2 Disubstitution prefers trans diequatorial to cis by 1.3 kcal/mol for diacid (roughly equivalent to the cyclohexyl analogue.) 145-155° a73 A single substituent prefers the equatorial position of the flap of the envelope (barrier ca. 3.4 kcal/mol, R = CH 3). Cyclopentane C2 Half-ChairCsEnvelope a73 Two lowest energy conformations (10 envelope and 10 half chair conformations C s favored by only 0.5 kcal/mol) in rapid conformational flux (pseudorotation) which causes the molecule to appear to have a single out-of-plane atom "bulge" which rotates about the ring. a73 Since there is no "natural" conformation of cyclopentane, the ring conforms to minimize interactions of any substituents present. a73 1,2 Disubstitution prefers trans for steric/torsional reasons (alkyl groups) and dipole reasons (polar groups). CsEnvelope Conformational Analysis: Cyclic Systems-2 CsEnvelope a73 A carbonyl or methylene prefers the planar position of the half-chair (barrier 1.15 kcal/mol for cyclopentanone). a73 1,3 Disubstitution: Cis-1,3-dimethyl cyclopentane 0.5 kcal/mol more stable than trans. H HH H O NaBH4 O O O OEt O O H H H H NaBH4 O OEt OH H H H H OH H OH H HH H O O "Reactions will proceed in such a manner as to favor the formation or retention of an exo double bond in the 5-ring and to avoid the formation or retention of the exo double bond in the 6-ring systems." Brown, H. C., Brewster, J. H.; Shechter, H. J. Am. Chem. Soc. 1954, 76, 467. Methylenecyclopentane and Cyclopentene hydrolyzes 13 times faster than Strain trends: > > a73 Decrease in eclipsing strain more than compensates for the increase in angle strain. Relative to cyclohexane derivatives, those of cyclopentane prefer an sp2 center in the ring to minimize eclipsing interactions. k6 k6 k5 = 23 95.5:4.5 keto:enol 76:24 enol:keto Brown, H. C., Brewster, J. H.; Shechter, H. JACS 1954, 76, 467. Brown, H. C.; Ichikawa, K. Tetrahedron 1957, 1, 221. Conan, J-Y.; Natat, A.; Priolet, D. Bull. Soc. Chim., Fr. 1976, 1935. ≈ Examples: Chair Half-Chair Boat Twist Boat +5.5 10.7-11.5 +1.0–1.5 Cyclohexane Energy Profile (kcal/mol) Inverted Chair Evans, Kim, Breit Chem 206Conformational Analysis: Cyclic Systems-3 k5 E = 0 E = +5.5 E = +6.5-7.0 The barrier: +10.7-11.5 +5.5 R H C HH MeH Me H R H C C Me H H H H H CMe Me Me H H HH H R H H MeH H SiMe Me Me H H R H MeMe H SnMe Me Me H Me MeMe H Monosubstituted Cyclohexanes: A Values Keq ?G° = –RTlnK eq a73 The A– Value, or -?G°, is the preference of the substituent for the equatorial position. a73 Me - axial has 2 gauche butane interactions more than Me-equatorial.Expected destabilization: ≈ 2(0.88) kcal/mol = ~1.8 kcal/mol; Observed: 1.74 kcal/mol A Values depend on the relative size of the particular substituent. 1.74 1.80 2.15 5.0 Evans, Breit Chem 206Conformational Analysis: Cyclic Systems-4 A–Value The "relative size" of a substituent and the associated A-value may not correlate. For example, consider the –CMe 3 and –SiMe 3 substituents. While the –SiMe 3substituent has a larger covalent radius, is has a smaller A-value: 4.5-5.0 2.5 1.1A–Value Can you explain these observations? a73 The impact of double bonds on A-values: Lambert, Accts. Chem. Res. 1987, 20, 454 R = Me substituent A-value(cyclohexane) 0.8 1.74 R = OMe 0.8 0.6 R = OAc 0.6 0.71 ??G° The Me substituent appears to respond strictly to the decrease in nonbonding interactions in axial conformer. With the more polar substituents, electrostatic effects due to the trigonal ring carbon offset the decreased steric environment. Chem 206D. A. Evans Bond Lengths and A-Values of Methyl Halides C–Cl: 1.79 ? C–Br: 1.95 ? C–I: 2.16 ?C–F: 1.39 ? F A-value: 0.25–0.42 Cl A-value: 0.53–64 Br A–value: 0.48-0.67 I A-value: 0.47–0.61 Chem 3D Pro (Verson 5.0) CMe3 H O Me3C CHMe2 H O Me3C Me H O Me3C Me H O H Me O H Me O Me3C H CMe3 O Me3C H CHMe2 O Me3C Me Me Me Me H X Me H X H Me H H Me Me H Me Me MeMe Me X HH Me H XH Me Me HH H H Evans, Breit Chem 206Conformational Analysis: Cyclic Systems-5 a73 Let's now compare look at the carbonyl analog in the 3-position The impact of trigonal Carbon ?G° = –1.36 kcal/molversus –1.74 for cyclohexane a73 Let's now compare look at the carbonyl analog in the 2-position ?G° = –1.56 kcal/molversus –1.74 for cyclohexane ?G° = –0.59 kcal/molversus –2.15 for cyclohexane However, the larger alkyl groups do not follow the expected trend. Can you explain? (see Eliel, page 732) ?G° = –1.62 kcal/mol versus –5.0 for cyclohexane Polysubstituted Cyclohexane A Values 1,4 Disubstitution: A Values are roughly additive. ?G° = –2(1.74) = –3.48 kcal/mol 1,3 Disubstitution: A Values are only additive in the trans diastereomer ?G° = 0 kcal/mol a73 As long as the substituents on the ring do not interact in either conformation, their A-values are roughly additive ?G° = A(Me) – A(X) The new interaction! For X = Me + 3.7 + 0.88+ 0.88 ?G° = 2(.9) + 1(+3.7)= 5.5 kcal/mol base epimerization base epimerization base epimerization A Me Ph C B Me Ph D EtO O n-C4H9 H OH H MeMe H H Me Me HH LiNR2 MeI Me Me H H EtO MeO n-C4H9 H OH H Me MeH H Evans, Breit Chem 206Conformational Analysis: Cyclic Systems-6 Let's now consider geminal substitution ?G° = A(Ph) – A(Me)The prediction: ?G° = +2.8 – 1.7 = +1.1 kcal/mol Observed: ?G° = –0.32 kcal/mol Hence, when the two substituents are mutually interacting you can predict neither the magnitude or the direction of the equilibrium. Let's analyze this case. ?G° = +2.8 ?G° = –0.32 Allinger, Tet. Lett. 1971, 3259 The conformer which places the isopropyl group equatorial is much more strongly preferred than would be suggested by A- Values. This is due to a syn pentane OH/Me interaction. Let's now consider vicinal substitution ?G° = 1 gauche butane – 2A(Me)The prediction: ?G° = +0.88 – 2(1.74) = +2.6 kcal/mol Observed: ?G° = +2.74 kcal/mol If the added gauche butane destabilization in the di-equatorial conformer had not been added, the estimate would have been off. Case 1: Case 2: D. Kim & Co-workers, Tetrahedron Lett. 1986, 27, 943. diastereoselection 89:11 Problem:Can you rationalize the stereochemical outcome of this reaction? Note the difference in the Ph substituent in A & B. Me H O Me H H O Me H O Me H N Me HH H N Me H H N Me HH H Me N H MeH O H Me N H Me H O H Me O H Me N H MeH O OH Me N Me N H O O Me H O OMe H O O H Me N Me N H Evans, Breit Chem 206Conformational Analysis: Cyclic Systems-7 Heteroatom-Substituted 6-Membered Rings ??G° = 1.74 kcal/mol Reference: G° = 2.86 kcal/mol ??G° = 1.43 kcal/mol ??G° = 1.95 kcal/mol G° = 2.5 kcal/mol ??G° = 1.6 kcal/mol ??G° = 1.9 kcal/mol A-Values for N-Substituents in Piperidine ??G° = 0.36 kcal/mol The Reference: ??G° = 3.0 kcal/mol a73 Hydrogen is "bigger" than the N–lone Pair. a73 The A-value of N–substituents is slightly larger than the corresponding cyclohexane value. Rationalize ??G° = 4.0 kcal/mol ??G° = 0.8 kcal/mol a73 The indicated distance is 2.05 ?. The analogous H–H distance in Cyclohexane is 2.45 ? (1) (2) (3) (4) (5) (6) 2.05 ? 2.45 ? a73 A-values at the 2-position in both the O & N heterocycles are larger than expected. This is due to the shorter C–O (1.43 ?), and C–N (1.47 ?) bond lengths relative to carbon (C–C; 1.53 ?). The combination of bond length and bond angle change increases the indicated 1,3-diaxial interaction (see eq 1, 4). Me Me H H H O Me H H H H H H H H H H H H H H H HMe H H R DC BA A B Me H H H H H C H H HMe HH R D Evans, Breit Chem 206Conformational Analysis: Bicyclic Ring Systems Conformations of Bicyclic Ring Systems The steroid nucleus provided the stimulation for the development of conformational analysis, particularly of polycyclic ring systems. D. H. R. Barton was awarded a Nobel prize in 1969 for his contributions in this area. 2.4 kcal/mol 0 Relative ?G° rigid Decalin Ring System (6/6) mobile Let's identify the destabilizing gauche butane interactions in the cis isomer 1 2 3 4 Gauche-butane interactions C1 C2 C1 C3 C4 C3 ?G°(est) = 3(0.88) = 2.64 kcal/mol Estimate the energy difference between the two methyl-decalins shown below. Hydrindane Ring System (6/5) flexible rigid ?G° = –0.5 kcal/mol a73 The turnover to favor the cis fusion results from the entropic preference for the less ordered cis isomer. The 5-5 Ring System favored A/B CisA/B Trans Rationalize the conformational flexibility of a A/B Trans vs. A/B Cis Steroid! 1 4 7 11 10 13 14 17 ?G° = +6.4 kcal/mol see Elier, p 780 Me3C CO2Et H Me3C CO2Et H TS TSMe3C CO2H H TSMe3C CO2H H CO2H HCO2H H H OHMe Me Me OH HMe Me Me Me3C OH H Me3C OH H Me3C OH H Me3C OH H OH H OH H Me3C OTs H Me3C OTs H Evans, Breit Chem 206Conformational Analysis: Axial vs Equatorial Reactivity The axial diastereomer is not always slower reacting: Different reactivity for axial and equatorial substituents a73 Acetylation with Ac2O/Py k rel 1 0.13 1 0.27 1 0.04 1 0.05 Axial substituents are more hindered, thus less reactive in many transformations k rel a73 Acid-catalyzed esterification k rel k rel a73 Ester Saponification 20 1k rel a73 Alcohol Oxidation with Cr(6+) 1 3.2k rel 1 3.36k rel The rate-determining step is breakdown of the chromate ester. This is an apparent case of strain acceleration a73 SN2 Reactions (Displacement with Ph–S–) 1 31k rel GSReference Case ?G ref?G A ?GA > ?G ref ??G° ??G > ??G° ?GB < ?G ref ?G B ??G° ??G < ??G° Steric Hindrance and Steric Assistance GS GS For a more detailed discussion of this topic see:Eliel, E. L., S. H. Wilen, et al. (1994). Stereochemistry of Organic Compounds pp 720-726 Evans, Breit Chem 206Conformational Analysis: Cylcoheptane See Eliel, page 762+ Cycloheptane Chair (2.16 kcal/mol) Twist-Chair (0 kcal/mol) Boat (3.02 kcal/mol) Twist-Boat (2.49 kcal/mol) Hendrickson, J. B. JACS 1961, 83, 4537. Olefins are preferentially orientated to eliminate eclipsing interactions. Chair-BoatLowest-energy conformation Cyclooctane 1 7 3 Ring strain originates in eclipsing interactions and transannular van der Waals interactions Transannular strain between C3 & C7 Methyl position 1 2 3 4 5 1.8 2.8 >4.5 -0.3 6.1(pseudoeqatorial)(pseudoaxial) (kcal/mol)?G 5 1 7 3 Underside view of boat-chair C3 & C7 eclipsing interactions 3 7 O X X O Me O Me MeI LiCuMe2 O Me Me O Me Me Evans, Breit Chem 206Conformational Analysis: Cyclooctane Cyclooctane continued... Chair-Boat (BC)Lowest-energy conformation 1 7 3 Transannular strain between C3 & C7 5 Cyclooctane derivatives Nu Nu Disubstitution occurs at C4 or C6 SN2 occurs at C1 and C5 Carbonyl is positioned at C3 or C7 Olefin is positioned at C3-C4 or C6-C7 Still, W. C.; Galynker, I. Tetrahedron 1981, 37, 1981. Chair-Chair (CC) conformation (+1-1.6 kcal/mol) Boat-Boat (BB) conformation (>+ 8 kcal/mol) Chair-Boat (CB) conformationreference structure LINR2 Predict stereochemistry a70 a70 Predict stereochemistry Methyl position 1 2 3 4 5 1.8 2.8 >4.5 -0.3 6.1(pseudoeqatorial)(pseudoaxial) (kcal/mol)?G H HO H HO H HO H HO H HLiO H HLiO H HLiO H HLiO H HLiO H HLiO H HLiO H HLiO H ΦR H C HH Me Me ΦO Φ 56 56 ΦM 56 B ΦP 56 C A Me Me CCC∠ 109° 28' ΦP ΦO ΦM –H2 Φ = 60° +6° For ΦP 5656 56 56 56 0* For ΦM 15° Φ = 56° –11° 44° 61 44 15 CCC∠ 111° 61° [?] +6° –41° –11° D. A. Evans Chem 206Conformational Transmission Observation: Relative enolate stability correlates to ring junction stereochemistry base ratio: 13 : 87 House, JOC 1965, 30, 1341 base ratio: 70 : 30 base ratio: 10 : 90 base ratio: 92 : 8 Observation: Relative enolate stability seems to be correlated to position of C=C Readings: Velluz etal, Angew. Chemie, Int Ed. 1965, 4, 181-270 How do we explain the experimental observations shown above? Let Φ be defined as the torsion or dihedral angle for butane Φ illustrated may be designated as Φ B. Let's now consider cyclohexane Perfect chair real chair Given cyclohexane with an identified torsion angle ΦR, if ΦR either increases or decreases wht effects in angle change are transmitted to ΦO, ΦM, and ΦP? ΦR = 56° ΦR = 0° Operation: Hence, relative to cyclohexane, the following notation for torsion angle change may be denoted: [?] = ΦR( 0°) – ΦR( 56°) R R R R B A R R B H H H H A R R B R R C R H Me H Me C R H Me H Me H HO H HO O OBz O Me OH Me Me C5H11 Ac2OTsOH H HLiO H HLiO AcO OBz O Me OH Me Me C5H11 H HLiO H HLiO AcO OBz D. A. Evans Chem 206Conformational Transmission-2 Operation: Operation: Simple Application: Reinforcing Torsional Effects versus Which C=C bond isomer is more stable? 1) C=C will open up ring=B torsion angle 2) Ring B will resist increase in its ring fusion torsion angle 3) Therefore torsion effects are opposed 1) C=C will close down ring=B torsion angle 2) Ring B will accomodate decrease in its ring fusion torsion angle 3) Therefore torsion effects are reinforcing base ratio: 10 : 90 base ratio: 92 : 8 effects reinforcingeffects opposing effects reinforcing effects opposing Question: Which is the more stable C=C isomer in the two THC structures? R. W. Kierstead, JACS 1967, 89, 5934 Question: Which enol acetate is more stable? or