D.A. Evans Conformational Analysis: Part -3 Chem 206 Conformational Analysis of Cyclic Systems http://www.courses.fasharvard.edu/-chem206/ Three Types of Strain Cher Prelog Strain: van der Waals interactions Baeyer Strain: bond angle distortion away from the ideal Advanced Organic Chemistry Pitzer Strain: torsional rotation about a sigma bond Lecture number 6 Baeyer Strain for selected ring sizes size of ring Ht of Combustion Total Strain Strain per CH2 "angle strain" ol(kcal mol) deviation from 109 28 4998 24°44 Conformational analysis-3 26.3 9°44 9448 5°16 Cyclopropane 11083 1.21 Conformational Analysis of C4 >C& Rings 14296 126 140 10 1586.8 12.4 1.24 1743.1 11.3 12 18934 051.9 5.2 14 15 Reading Assignment for week Eliel, E. L, Wilen, S. H. Stereochemistry of Organic Compounds Chapter 11, John Wiley Sons, 1994 A. Carey Sundberg: Part A; Chapter 3 a Baeyer"angle strain "is calculated from the deviation of the planar bond angles from the ideal tetrahedral bond angle de meijere, "Bonding Properties of Cyclopropane their Chemical Characteristics Angew Chem. Int Ed. 1979, 18, 809-826(handout) a Discrepancies between calculated strain/CH2 and the"angle strain" results from puckering to minimize van der Waals or Snyder, J. P JACS, 2000, 122, 544 eclipsing torsional strain between vicinal hydrogens Why is there an increase in strain for medium sized rings even Monda though they also can access puckered conformations free of Matthew d shair September 30, 2002 angle strain? The answer is transannular strain-van der Waals interactions between hydrogens across the ring
D. A. Evans Chem 206 Matthew D. Shair Monday, September 30, 2002 http://www.courses.fas.harvard.edu/~chem206/ ■ 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 ■ Cyclopropane ■ 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' 3 4 5 6 7 8 9 10 11 12 13 14 15 499.8 656.1 793.5 944.8 1108.3 1269.2 1429.6 1586.8 1743.1 1893.4 2051.9 2206.1 2363.5 27.5 26.3 6.2 0.1 6.2 9.7 12.6 12.4 11.3 4.1 5.2 1.9 1.9 9.17 6.58 1.24 0.02 0.89 1.21 1.40 1.24 1.02 0.34 0.40 0.14 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. ■ Baeyer "angle strain" is calculated from the deviation of the planar bond angles from the ideal tetrahedral bond angle. ■ Discrepancies between calculated strain/CH2 and the "angle strain" results from puckering to minimize van der Waals or eclipsing torsional strain between vicinal hydrogens. ■ 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
Evans. Kim. Breit Cyclopropane: Bonding, Conformation, Carbonium lon Stabilization Chem 206 Cyclopropane Carbocation Stabilization via Cyclopropylgroups ■ Necessarily planar. Subtituents are therefore eclipsed a Disubstitution prefers to be trans ■ Almost sp2,not a rotational barrier of about NMR in super acids U=3080cm 13.7 kcal/mol is observed in 8(CH3)=2.6 and 3. 2 ppm following example Walsh Model for Strained Rings a Rather than o and gc-c bonds, cyclopropane has sp and p-type X-ray Structures support this orientation 1222A 1517A 1302A 1478A1474A 1464A 1541A t(antibonding 1409A 1444A Nonbonding A a-1(bonding) Angew Chem. Int Ed. 1979, 18, 809-826(handout R.F.Chds,JACS1986,108,1692
H H H H H H Nonbonding Ph O H H Me Me C R O Evans, Kim, Breit Cyclopropane: Bonding, Conformation, Carbonium Ion Stabilization Chem 206 Cyclopropane ■ Necessarily planar. ■ Subtituents are therefore eclipsed. ■ Disubstitution prefers to be trans. u = 3080 cm-1 j = 120 ° ■ Almost sp2 , not sp3 Walsh Model for Strained Rings: ■ Rather than s and s* c-c bonds, cyclopropane has sp2 and p-type orbitals instead. side view s–1 (bonding) s (antibonding) s (antibonding) p (antibonding) p (bonding) p (bonding) 3 Carbocation Stabilization via Cyclopropylgroups A rotational barrier of about 13.7 kcal/mol is observed in following example: NMR in super acids d(CH3 ) = 2.6 and 3.2 ppm R. F. Childs, JACS 1986, 108, 1692 1.464 Å 1.409 Å 1.534 Å 1.541 Å 1.444 Å 1.302 Å 1.222 Å 1.474 Å 1.517 Å 1.478 Å X-ray Structures support this orientation de Meijere, "Bonding Properties of Cyclopropane & their Chemical Characteristics" Angew Chem. Int. Ed. 1979, 18, 809-826 (handout)
Evans. Kim Breit Conformational Analysis: Cyclic Systems-2 Chem 206 Cyclobutane Cyclopentane 145-155° ax Eclipsing torsional strain overrides increased bond angle strain by I puckering 0=28° a Ring barrier to inversion is 1.45 kcal/mol C Envelope C2 Half-Chair CsEnvelope a Two lowest energy conformations(10 envelope and 10 half chair conformations 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 a Since there is no"natural"conformation of cyclopentane, the ring conforms to minimize interactions of any substituents present SeNven (MM2) LA single substituent prefers the equatorial position of the fiap of the envelope ■△G=1 kcal/mol favoring R= Me equatorial (barrier ca. 3. 4 kcal/mol, R= CH3) 1, 2 Disubstitution prefers 1, 3 Disubstitution prefers cis diequatorial to trans for steric/torsion ans by 0.58 kcal/mol for di-bromo cmpd reasons(alkyl groups) and Me 1,3 Disubstitution: Cis-1, 3-dimethyl ion prefers trans diequatorial to cyclopentane 0.5 kcal/mol more stable than trans nol for diacid (roughly equivalent to LA carbonyl or methylene prefers the planar position of the half-chair(barrier 1.15 kcal/mol for cyclopentanone)
H H H H H H H H H H H H H H H H H H H H H H H H H H H H H 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 j = 28 ° ■ Eclipsing torsional strain overrides increased bond angle strain by puckering. ■ Ring barrier to inversion is 1.45 kcal/mol. ■ G = 1 kcal/mol favoring R = Me equatorial ■ 1,3 Disubstitution prefers cis diequatorial to trans by 0.58 kcal/mol for di-bromo cmpd. ■ 1,2 Disubstitution prefers trans diequatorial to cis by 1.3 kcal/mol for diacid (roughly equivalent to the cyclohexyl analogue.) 145-155° ■ A single substituent prefers the equatorial position of the flap of the envelope (barrier ca. 3.4 kcal/mol, R = CH3 ). Cyclopentane C C2 Half-Chair sEnvelope ■ Two lowest energy conformations (10 envelope and 10 half chair conformations Cs 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. ■ Since there is no "natural" conformation of cyclopentane, the ring conforms to minimize interactions of any substituents present. ■ 1,2 Disubstitution prefers trans for steric/torsional reasons (alkyl groups) and dipole reasons (polar groups). CsEnvelope Conformational Analysis: Cyclic Systems-2 CsEnvelope ■ A carbonyl or methylene prefers the planar position of the half-chair (barrier 1.15 kcal/mol for cyclopentanone). ■ 1,3 Disubstitution: Cis-1,3-dimethyl cyclopentane 0.5 kcal/mol more stable than trans
Evans. Kim. breit Conformational Analysis: Cyclic Systems-3 Chem 206 Methylenecyclopentane and Cyclopentene Cyclohexane Energy Profile(kcal/mol) Strain trends Half-Chair a Decrease in eclipsing strain >人、△mmm) Relative to cyclohexane derivatives, those of cyclopentane prefer an sp center in the ring to minimize eclipsing interactions Reactions will proceed in such a as to favor the formation or retention of an exo double bond in the 5-ri the formation or retention of the exo double bond in the 6-ril Shechter H. J. Am. Chem 1954.76.467 Chair averted Chair k5 =23 H Brown. H. C. Ichikawa K. Tetrahedron 1957. 1. 221 △E=+657.0 drolyzes AE=+55 13 times faster than Conan J-Y: Natat, A: Prolet, D. Bull. Soc. Chim. Fr. 1976. 1935 The barrier: +10.7-11.5 E=0 95.5: 4.5 keto enol 76: 24 enol: keto Brown,HC,Brewster,JH:Shechter,H.JACS1954,76,467
H H H 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 H H 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: > > ■ 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 Conformational Analysis: Cyclic Systems-3 Chem 206 k5 E = 0 E = +5.5 E = +6.5-7.0 The barrier: +10.7-11.5 +5.5
Evans. Breit Conformational Analysis: Cyclic Systems-4 Chem 206 Monosubstituted Cyclohexanes: A Values A Values depend on the relative size of the particular substituent △7 R△G°=- reinKe a Me -axial has 2 gauche butane interactions more than Me-equatorial Expected destabilization: s 2(0.88 )kcal/mol =-1.8 kcal/mol; A-Value 1.74 180 5.0 Observed: 1.74 kcal/mol 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 3 ent radius is has a smaller A-value H a The A-Value, or-AG, is the preference of the substituent for the Me equatorial position Table 3.6. Conformational Free Energies(-AG )for ubstituent Groups Substituent -G°(kcal/mol)Ref. A-Value 4.5-5.0 2.5 1.1 Can CH a The impact of double bonds on A-values Lambert. Accts. Chem. Res. 1987. 20. 454 一C≡CH CAH -CN 0.15-0.25 A-value substituent AG° OH (aprotic solvents) OH (proti R 08 -OCH R=OMe HgB R=OAc 0 0.71 a. F.R. bicyclic Chem 3, 140(1971) The Me substituent appears to respond strictly to the decrease in nonbonding interactions L. A. Freiberg, J. Org. Chem 31, 804(1966) in axial conformer. With the more polar substituents, electrostatic effects due to the rigonal ring carbon offset the decreased steric environment. J. Org. Chem. 43
R H C H H Me H Me H R H C C Me H H H H H C Me Me Me H H H H H R H H Me H H Si Me Me Me H H R H Me Me H Sn Me Me Me H Me Me Me H Monosubstituted Cyclohexanes: A Values Keq DG° = –RTlnKeq ■ The A– Value, or -DG°, is the preference of the substituent for the equatorial position. ■ 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 Conformational Analysis: Cyclic Systems-4 Chem 206 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 3 substituent has a larger covalent radius, is has a smaller A-value: A–Value 4.5-5.0 2.5 1.1 Can you explain these observations? ■ 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 -DG° 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
D A. Evans Bond Lengths and A-Values of Methyl Halides Chem 206 c-F:139A c-C:179A C-Br: 1.95A C-:216A FA-value Cl A-value Br a-value I A-value 0.25-042 0.53-64 048067 047-0.61 Chem 3D Pro (Verson 5.0)
D. A. Evans Bond Lengths and A-Values of Methyl Halides Chem 206 C–F: 1.39 Å C–Cl: 1.79 Å C–Br: 1.95 Å C–I: 2.16 Å 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)
Evans. Breit Conformational Analysis: Cyclic Systems-5 Chem 206 The impact of trigonal Carbon Polysubstituted Cyclohexane A Values Lets now compare look at the carbonyl analog in the 3-position L As long as the substituents on the ring do not interact in either conformation, their A-values are roughly additive 1, 4 Disubstitution: A Values are roughly additive AG°=-1.36 kcal/mol versus-174 for cyclohexane AG°=0 kcal/mol Let's now compare look at the carbonyl analog in the 2-position epimerization △G°=-2(1.74)=-348 kcal/mol 1, 3 Disubstitution A Values are only additive in the trans diastereomer AG°=-1.56 kcal/mol ersus-174 for cyclohexane However, the larger alkyl groups do not follow the expected trend △G°=AMe)-A() Can you explain?(see Eliel, page 732) CHMe? CHMe? 小个x= AG°=-059 kcal/mol versus-2. 15 for cyclohexane The new interaction! For X= M +088 △G°=-162 kcal/mol +088 versus-5.0 for cyclohexane △G°=2(9)+1(+37)=5.5 kcal/mol +3.7
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 Me Me Me X H H Me H X H Me Me H H H H Evans, Breit Conformational Analysis: Cyclic Systems-5 Chem 206 ■ Let's now compare look at the carbonyl analog in the 3-position The impact of trigonal Carbon DG° = –1.36 kcal/mol versus –1.74 for cyclohexane ■ Let's now compare look at the carbonyl analog in the 2-position DG° = –1.56 kcal/mol versus –1.74 for cyclohexane DG° = –0.59 kcal/mol versus –2.15 for cyclohexane However, the larger alkyl groups do not follow the expected trend. Can you explain? (see Eliel, page 732) DG° = –1.62 kcal/mol versus –5.0 for cyclohexane Polysubstituted Cyclohexane A Values 1,4 Disubstitution: A Values are roughly additive. DG° = –2(1.74) = –3.48 kcal/mol 1,3 Disubstitution: A Values are only additive in the trans diastereomer DG° = 0 kcal/mol ■ As long as the substituents on the ring do not interact in either conformation, their A-values are roughly additive DG° = A(Me) – A(X) The new interaction! For X = Me + 3.7 + 0.88 + 0.88 DG° = 2(.9) + 1(+3.7)= 5.5 kcal/mol base epimerization base epimerization base epimerization
Evans. breit Conformational Analysis: Cyclic Systems-6 Chem 206 Let's now consider geminal substitution Let's now consider vicinal substitution Case 1: The prediction:△G°=A(Ph)-A(Me) △G°=+2.8-1.7=+1.1 kcal/ mol The prediction ob AG°=-0.32 kcal/mol △G°=+0.88-201.74)=+26 kcal/ mol predict neither ze this case Observed △G°=+2.74 kcal/mol Allinger, Tet. Lett. 1971, 3259 If the added gauche butane destabilization in the di-equatorial conformer had not been added the estimate would have been off Case 2. EMMe △G°=+2.8 AG°=-0.32 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 Problem: Can you rationalize the stereochemical outcome of this reaction? LiNR n-C4Hg' n-CAHg' diastereoselection 89: 11 Note the difference in the ph substituent in a& B D. Kim Co-workers. Tetrahedron Lett. 1986. 27. 943
A Me Ph C B Me Ph D EtO O n-C4H9 H OH H Me Me H H Me Me H H LiNR2 MeI Me Me H H EtO Me O n-C4H9 H OH H Me Me H H Evans, Breit Conformational Analysis: Cyclic Systems-6 Chem 206 Let's now consider geminal substitution The prediction: DG° = A(Ph) – A(Me) DG° = +2.8 – 1.7 = +1.1 kcal/mol Observed: DG° = –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. DG° = +2.8 DG° = –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 The prediction: DG° = 1 gauche butane – 2A(Me) DG° = +0.88 – 2(1.74) = +2.6 kcal/mol Observed: DG° = +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
Evans. Breit Conformational Analysis: Cyclic Systems-7 Chem 206 Heteroatom-Substituted 6-Membered Rings A-Values for N-Substituents in Piperidine L A-values at the 2-position in both the o&n heterocycles are larger thar expected. This is due to the shorter C-o(1.43 A), and c-N (1.47 A) bond lengths relative to carbon(C-C: 1.53 A). The combination of bond length and bond angle change increases the indicated 1, 3-diaxial interaction(see eq 1, 4) △G°=036 kcal/mol Me Reference NMe-△G°=174 kcal/mol -△G°=30 kcal/mo a Hydrogen is"bigger"than the N-lone Pair a The A-value of N-substituents is slightly larger than the corresponding Me-△G°=286 kcal/mol cyclohexane value. Rationalize e-△G°=143 carmol △G°=40 kcal/mol △=-1kam 6以一公 Me-△G°=25 kcal/mol I The indicated distance is 2. A. The analogous H-H distance in Cyclohexane is 2.45A G°=16 kcal/mol (6) NMe-△G°=19 kcal/mol 2.05A 245A
Me H O Me H H O Me H O Me H N Me H H H N Me H H N Me H H H Me N H Me H O H Me N H Me H O H Me O H Me N H Me H O O H Me N Me N H O O Me H O O Me H O O H Me N Me N H Evans, Breit Conformational Analysis: Cyclic Systems-7 Chem 206 Heteroatom-Substituted 6-Membered Rings -DG° = 1.74 kcal/mol Reference: G° = 2.86 kcal/mol -DG° = 1.43 kcal/mol -DG° = 1.95 kcal/mol G° = 2.5 kcal/mol -DG° = 1.6 kcal/mol -DG° = 1.9 kcal/mol A-Values for N-Substituents in Piperidine -DG° = 0.36 kcal/mol The Reference: -DG° = 3.0 kcal/mol ■ Hydrogen is "bigger" than the N–lone Pair. ■ The A-value of N–substituents is slightly larger than the corresponding cyclohexane value. Rationalize -DG° = 4.0 kcal/mol -DG° = 0.8 kcal/mol ■ The indicated distance is 2.05 Å. The analogous H–H distance in Cyclohexane is 2.45 Å (1) (2) (3) (4) (5) (6) 2.05 Å 2.45 Å ■ 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 Å), and C–N (1.47 Å) bond lengths relative to carbon (C–C; 1.53 Å). The combination of bond length and bond angle change increases the indicated 1,3-diaxial interaction (see eq 1, 4)
Evans. breit Conformational Analysis: Bicyclic Ring Systems Chem 206 Conformations of Bicyclic Ring Systems Estimate the energy difference between the two methyl-decalins shown beloy see Elier, p 780 Hydrindane Ring System(6/5) The steroid nucleus provided the stimulation for the conformational analysis, particularly tems. D.H. R. Barton was awarded a nobel prize in 1969 for his contributions in this area flexible igid Decalin Ring System(6/6) AG°=-0.5kcam mobile H I The turnover to favor the cis fusion results from the entropic preference for the less ordered cis isomer The 5-5 Ring System 2 4 kcal/mol 0 Relative△G AG°=+64 kcal/mol Let's identify the destabilizing gauche butane interactions in the cis isomer Gauche-butane interactions c1→c2 c1→c3 c4→c3 AB Trans AB Cis G(est)=3(0.88)=2.64 kcal/mol Rationalize the conformational flexibility of a AB Trans Vs. AB Cis Steroid
Me Me H H H O Me H H H H H H H H H H H H H H H Me H H H R C D A B A B Me H H H H H C H H Me H H H R D Evans, Breit Conformational Analysis: Bicyclic Ring Systems Chem 206 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 DG° 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 DG°(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 DG° = –0.5 kcal/mol ■ 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 Trans A/B Cis Rationalize the conformational flexibility of a A/B Trans vs. A/B Cis Steroid! 1 4 7 11 10 13 14 17 DG° = +6.4 kcal/mol see Elier, p 780