哈佛大学：《高等有机化学》课程教材讲义（英文版）Lecture 4 Organic Compounds

D.A. Evans Acyclic Conformational Analysis-1 Chem 206 Useful Literature Reviews http://www.courses.fasharvardedu/-chem206/ ElieL, E L, S.H. Wilen, et al. (1994). Stereochemistry of Organic Compounds Chemistry 206 Juaristi, E (1991). Introduction to Stereochemistry and Conformational Analysis Juaristi, E, Ed (1995) Advanced organic chemistr amics and stere m chweizer, W.B. (1994). Conformational Analysis Structure Correlation, Vol Lecture Number 4 Verlagsgesellschaft: 369-404 Acyclic Conformational Analysis-1 Kleinpeter, E (1997). "Conformational Analysis of Saturated Six-Membered xygen-Containing Heterocyclic Rings Adv. Heterocycl. Chem.69:217-69 Ethane Propane, Butane Pentane Conformations i Glass, R.R Ed mational Analysis of Medium-Sized Ring les. Weinheim vch Introduction to Allylic Strain Bucourt, R (1973). The Torsion Angle Concept in Conformational Analysis Top. Stereochem. 8: 159 a Reading Assignment for week A. Carey& Sundberg: Part A; Chapters 2&3 /'-- ■ Problems of the Day R. W. Hoffmann, Chem. Rev. 1989 Allylic 1-3-Strain as a controlling ent in stere tive transformations Predict the most conformation of the R. W. Hoffmann, Angew. Chem. Int. Ed. Engl. 2000, 39, 2054-2070 Conformation Design of Open-Chain Compounds F Weinhold, Angew. Science 2001, 411, 539-541 OTs Wednesday Matthew D. shair eptember 25, 2002 Eto LiNE i n-C4H n-cAHg A diastereoselection 98:2

D. A. Evans Chem 206 Useful LIterature Reviews ■ Problems of the Day Matthew D. Shair Wednesday, September 25, 2002 http://www.courses.fas.harvard.edu/~chem206/ Bucourt, R. (1973). “The Torsion Angle Concept in Conformational Analysis.” Top. Stereochem. 8: 159. Chemistry 206 Advanced Organic Chemistry Lecture Number 4 Acyclic Conformational Analysis-1 ■ Ethane, Propane, Butane & Pentane Conformations ■ Introduction to Allylic Strain ■ Reading Assignment for week A. Carey & Sundberg: Part A; Chapters 2 & 3 Glass, R. R., Ed. (1988). Conformational Analysis of Medium-Sized Ring Heterocycles. Weinheim, VCH. Juaristi, E. (1991). Introduction to Stereochemistry and Conformational Analysis. New York, Wiley. Juaristi, E., Ed. (1995). Conformational Behavior of Six-Membered Rings: Analysis, Dynamics and Stereochemical Effects. (Series: Methods in Stereochemical Analysis). Weinheim, Germany, VCH. Kleinpeter, E. (1997). “Conformational Analysis of Saturated Six-Membered Oxygen-Containing Heterocyclic Rings.” Adv. Heterocycl. Chem. 69: 217-69. Schweizer, W. B. (1994). Conformational Analysis. Structure Correlation, Vol 1 and 2. H. B. Burgi and J. D. Dunitz. Weinheim, Germany, V C H Verlagsgesellschaft: 369-404. Eliel, E. L., S. H. Wilen, et al. (1994). Stereochemistry of Organic Compounds. New York, Wiley. O O Predict the most stable conformation of the indicated dioxospiran? R. W. Hoffmann, Chem. Rev. 1989, 89, 1841-1860 Allylic 1-3-Strain as a Controlling Element in Stereoselective Transformations diastereoselection 98:2 EtO Me O n-C4H9 OTs H H n-C4H9 O Me EtO Can you predict the stereochemical outcome of this reaction? Acyclic Conformational Analysis-1 R. W. Hoffmann, Angew. Chem. Int. Ed. Engl. 2000, 39, 2054-2070 Conformation Design of Open-Chain Compounds F. Weinhold, Angew. Science 2001, 411, 539-541 "A New Twist on Molecular Shape" LiNR2

D A. Evans Acyclic Conformational Analysis-1 Chem 206 Ethane rotational/ Barrier: The FMo view The following discussion is intended to provide a general: F Weinhold, Angew. Science 2001, 411, 539-541A New Twist on Molecular Shape overview of acyclic conformational analysis steric argument for the barrier untenable Ethane Propane The conformational isomerism in these 2 structures reveals a gratify ing levelof possible in the staggered conformation than in the eclipsed conformation as intemal consistency In the staggered conformation there are 3 anti-periplanar C-H Bonds eclipsed conformation 0 AE=+3.0 kcal moP(R=H) Van derWaals radi of vicinal hydrogens HOMO In the eclipsed conformation there are 3 syn-periplanar C-H Bonds staggered ation In propane there is a discernable For purposes of analysis, each eclipsed conformer may be broken up into its Following this argument one might conclude that component destabilizing interactions a The staggered conformer has a better orbital match between bonding and antibonding states Incremental Contributions to the barrier Structure Eclipsed atoms &E(kcal mol") a The staggered conformer can form more delocalized molecular orbitals J. P. Lowe was the first to propose this explanation ethane (H+H) +1.0 kcal mol A Simple Molecuar Orbital Explanation for the Barrier to Internal 2(H+>H) +1.0 kcal mol-1 Rotation in Ethane and other molecules" propane J.P.Lowe,JAcs1970,92,3799 1(H+Me) +1.4 kcal mol-1 Calculate the the rotational barrier about the c1-c2 bond in isobutane

D. A. Evans Acyclic Conformational Analysis-1 Chem 206 The following discussion is intended to provide a general overview of acyclic conformational analysis Ethane & Propane The conformational isomerism in these 2 structures reveals a gratifying level of internal consistency. D E = +3.4 kcal mol-1 (R = Me) staggered conformation D E = +3.0 kcal mol-1 (R = H) +1.4 kcal mol -1 +1.0 kcal mol -1 Incremental Contributions to the Barrier. +1.0 kcal mol -1 1 (H«Me) 2 (H«H) 3 (H«H) propane ethane d E (kcal mol -1 Structure Eclipsed atoms ) For purposes of analysis, each eclipsed conformer may be broken up into its component destabilizing interactions. Van derWaals radii of vicinal hydrogens do not overlap in ethane In propane there is a discernable interaction Ethane Rotational Barrier: The FMO View One can see from the space-filling models that the Van der Waals radii of the hydrogens do not overlap in the eclipsed ethane conformation. This makes the steric argument for the barrier untenable. One explanation for the rotational barrier in ethane is that better overlap is possible in the staggered conformation than in the eclipsed conformation as shown below. s* C–H LUMO s C–H HOMO In the staggered conformation there are 3 anti-periplanar C–H Bonds s C–H HOMO s* C–H LUMO s C–H s* C–H In the eclipsed conformation there are 3 syn-periplanar C–H Bonds s* C–H s C–H Following this argument one might conclude that: R C H H C H H H H R H H H H C C C C C H C H C C H H Me Me Me Calculate the the rotational barrier about the C1-C2 bond in isobutane H H eclipsed conformation ■ The staggered conformer has a better orbital match between bonding and antibonding states. ■ The staggered conformer can form more delocalized molecular orbitals. J. P. Lowe was the first to propose this explanation "A Simple Molecuar Orbital Explanation for the Barrier to Internal Rotation in Ethane and Other Molecules" J. P. Lowe, JACS 1970, 92, 3799 F. Weinhold, Angew. Science 2001, 411, 539-541"A New Twist on Molecular Shape" H H

D. A. Evans Acyclic Conformational Analysis: Butane Chem 206 The 1.2-Dihaloethanes Butane X= CI: AH=+0.9-1.3 kcal/mol Using the eclipsing interactions extracted from propane ethane we should be X=Br, AH=+1.4-1.8 kcal/mo/ , able to estimate all but one of the eclipsed butane conformations X=F;△H°=-0.6-0.9 kcal/mol taggered eclipsed conformation conformation Observation: While the anti conformers are favored for X =Cl, Br, the gauche AE=? conformation is prefered for 1, 2-difluroethane. Expla s with class the origin of the gauche stabilisation of the difluoro anaolg Eclipsed atoms 8E(kcal mol " Relationship between AG and Keg and pKa 1 (H+H) +1.0 kcal mol-1 +2. 8 kcal mol Recall that △G°=- RTL k △Eest=38 kcal mol △G=-23 RT Log1oK The estimated value of +3.8 agrees quite well with the value of +3.6 reported At 298 K: 2.3RT=1.4(AG in kcal Mor1) by Allinger(J Chem.1980.1,181-184) A G 1. 4 locKe n-Butane Torsional Energy Profile Logue △G298=14pKeq Hence, pK is proportional to the free energy change Keq pKeq△G 1000 太 36 10 +088 Ref=o -2. 8 kcal/mol

D. A. Evans Acyclic Conformational Analysis: Butane Chem 206 The 1,2-Dihaloethanes X = Cl; DH° = + 0.9–1.3 kcal/mol X = Br; DH° = + 1.4–1.8 kcal/mol X = F; DH° = – 0.6-0.9 kcal/mol Observation: While the anti conformers are favored for X = Cl, Br, the gauche conformation is prefered for 1,2-difluroethane. Explain. X C X H H H H H C X H H H X Discuss with class the origin of the gauche stabiliation of the difluoro anaolg. pKeq 0 -1 -2 0 –1.4 1.0 10 100 Keq DG˚ D G˚298 = 1.4 pKeq pKeq = – Log10Keq D G˚298 = –1.4 Log10Keq D G˚ = –2.3RT Log10K At 298 K: 2.3RT = 1.4 (DG in kcal Mol–1 ) D G° = –RT Ln K Relationship between DG and Keq and pKa –2.8 kcal /mol Recall that: or Since Hence, pK is proportional to the free energy change +3.6 +5.1 +0.88 Ref = 0 G E1 E2 n-Butane Torsional Energy Profile D E = ? Eclipsed atoms d E (kcal mol -1) +1.0 kcal mol 1 (H«H) -1 +2.8 kcal mol 2 (H«Me) -1 D E est = 3.8 kcal mol -1 The estimated value of +3.8 agrees quite well with the value of +3.6 reported by Allinger (J. Comp. Chem. 1980, 1, 181-184) eclipsed conformation staggered conformation Using the eclipsing interactions extracted from propane & ethane we should be able to estimate all but one of the eclipsed butane conformations Butane H C Me H H H Me C Me H H H Me H Me C Me C H H H H H H H H Me Me Me C Me H C H H H H H H H Me Me energy A

D. A. Evans Acyclic Conformational Analysis: Butane Chem 206 Butane continued From the torsional energy profile established by Allinger, we should be able to Nomenclature for extract the contribution of the Mee Me eclipsing interaction to the barrier taggered conformers trans or t gauche(+) gauche() staggered eclipsed or g conformation conformation her population at 298 K 15% 5% AE=+5.1 kcal mol General nomenclature for diastereomers resulting from rotation about a single bond (Klyne, Prelog, Experientia 1960, 16, 521-) Let's extract out the magnitide of the Me-Me interaction 2(HH+1(MeMe)=+5.1 1(MeMe)=+5.1-2(HH) 1(MeMe)=+3.1 太 Incremental Contributions to the barrier Eclipsed atoms &E(kcal mol.) +2.2 From the energy profiles of ethane, propane, and n-butane, one may extract i the useful eclipsing interactions summarized below Hierarchy of Eclipsing Interactions 太 X-Y 8E kcal mol H-H Torsion angle Butane 0±30 HOMe +14 i Energy Maxima i Energy Minima +60±30° syn-clinal +sc(g+)6 Me-Me +3.1 E ap(anti or t A 20±30

From the energy profiles of ethane, propane, and n-butane, one may extract the useful eclipsing interactions summarized below: Hierarchy of Eclipsing Interactions d E kcal mol -1 +1.0 +1.4 +3.1 eclipsed conformation staggered conformation +2.2 Incremental Contributions to the Barrier. +2.0 1 (Me«Me) 2 (H«H) d E (kcal mol -1 Eclipsed atoms ) D E = +5.1 kcal mol-1 From the torsional energy profile established by Allinger, we should be able to extract the contribution of the Me«Me eclipsing interaction to the barrier: Butane continued D. A. Evans Acyclic Conformational Analysis: Butane Chem 206 Me C H C H H H Me Me H H Me H H C C X Y H H H H X Y H H H Me Me Me Eclipsed Butane conformation General nomenclature for diastereomers resulting from rotation about a single bond R C R R C R R C R sp sc (Klyne, Prelog, Experientia 1960, 16, 521.) sc ac ac ap C R R C R R C R R 0° +60° +120° 180° -60° -120° Torsion angle Designation Symbol 0 ± 30° +60 ± 30° +120 ± 30° 180 ± 30° -120 ± 30° -60 ± 30° ± syn periplanar + syn-clinal + anti-clinal antiperiplanar - anti-clinal - syn-clinal ± sp + sc (g+) + ac ap (anti or t) - ac - sc (g-) Energy Maxima Energy Minima E2 G E1 A E1 G n-Butane Conformer Nomenclature for staggered conformers: C H H H H Me Me C H H Me H H Me C H Me H H H Me trans or t or (anti) gauche(+) or g+ gauche(-) or g￾Conformer population at 298 K: 70% 15% 15% Let's extract out the magnitide of the Me–Me interaction 2 (H«H) + 1 (Me«Me) = +5.1 1 (Me«Me) = +5.1 – 2 (H«H) 1 (Me Me) = +3.1

D. A. Evans Acyclic Conformational Analysis: Pentane Chem 206 n-Pentane Rotation about both the C2-C3 and C3-C4 bonds in either direction(+or-:: The double-gauche pentane conformation The new high-energy conformation:(9g) Estimate of 1, 3-Dimethyl Eclipsing Interaction AG°=X+2 Y where 1(t 2(g X=1,3(Me> Me)&Y=1, 3(Me+H) Ant(2.3)-Ant(34) Gauche(23)-An“(34) 1,3(Me+H)=Skew-butane=0.88 kcal mol -1 13MeMe)=△G°-2Y=55-1,76=+37 kcal mol 1, 3(Me+- Me)=+3.7 kcal mol-1 Estimates of In-Plane 1, 2&1, 3-Dimethyl Eclipsing Interactions 4(g’g) 3(g’g Gauche e(2, 3)-Gauche'(3, 4)+ Gauche (2, 3)-Gauche(3, 4) double gauche pentane 3.7 3.9 76 It may be concluded that in-plane 1, 3(Me+Me)interactions are Ca +4 cal/mol while 1, 2(Me>Me)interactions are destablizing by Ca 2.2 kcal/mol

~ 2.2 It may be concluded that in-plane 1,3(Me«Me) interactions are Ca +4 kcal/mol while 1,2(Me«Me) interactions are destabliizing by Ca 2.2 kcal/mol. ~ 3.7 ~3.9 ~ 7.6 Estimates of In-Plane 1,2 &1,3-Dimethyl Eclipsing Interactions 1,3(Me«Me) = + 3.7 kcal mol -1 D G° = +5.5 kcal mol -1 D G° = X + 2Y where: X = 1,3(Me«Me) & Y = 1,3(Me«H) Estimate of 1,3-Dimethyl Eclipsing Interaction 1,3(Me«Me) = D G° – 2Y = 5.5 –1.76 = + 3.7 kcal mol -1 1,3(Me«H) = Skew-butane = 0.88 kcal mol -1 The double-gauche pentane conformation n-Pentane D. A. Evans Acyclic Conformational Analysis: Pentane Chem 206 Me Me Me Me Me Me Me Me Me Me H H H H Me H H H H Me Me H H Me H H Me Me Me Me Me Me Me Me Me Me Me Me Rotation about both the C2 -C3 and C3 -C4 bonds in either direction (+ or -): tg+ g-g+ g-t g-g￾tg￾g+g￾g+t g+g+ t,t From prior discussion, you should be able to estimate energies of 2 & 3 (relative to 1). On the other hand, the least stable conformer 4 requires additional data before is relative energy can be evaluated. Anti(2,3)-Anti(3,4) 1 1 1 1 3 3 3 3 5 5 5 5 Gauche(2,3)-Anti(3,4) Gauche(2,3)-Gauche'(3,4) Gauche(2,3)-Gauche(3,4) double gauche pentane 1 (t,t) 4 (g+g – ) 3 (g+g + ) 2 (g+ t) The new high-energy conformation: (g+g – ) X Y

D. A. Evans Acyclic Conformational Analysis: Natural Products Chem 206 The syn-Pentane Interaction -Consequences Lactol& Ketol Polyether Antibioitics ( R W. Hoffmann,ACE199231,1124-1134) The conformation of these structures are strongly influenced by the acyclic stereocenters gg Ferensimycin B, R= Me Me hh R Lysocellin, R=H The conformation of these structures are strongly influenced by the Consequences for the preferred conformation of polyketide natural products acyclic stereocenters and intemal H-bonding Analyze the conformation found in the crystal state of a bourgeanic acid derivative Alborixinr= Me: X-206R=H Internal H-Bondin OH O MeMe Me oH MeOH Bourgeanic acid OOH Metal ion ligation sites(M=Ag, K) Me Synthesis: Evans, Bender, Morris, JACS 1988, 110, 2506

D. A. Evans Acyclic Conformational Analysis: Natural Products Chem 206 The syn-Pentane Interaction - Consequences (R. W. Hoffmann, ACIE 1992, 31, 1124-1134.) R R' Me Me R R' Me Me R R' Me H H Me Me Me H R R' H R Me Me H H R' Me R' H H R H º º tt g -g - tg gt or or Consequences for the preferred conformation of polyketide natural products Analyze the conformation found in the crystal state of a bourgeanic acid derivative! Me Me Me OH Me O OR Bourgeanic acid Ferensimycin B, R = Me Lysocellin, R = H Lactol & Ketol Polyether Antibioitics R HO O O O Me Me OH O Et Me OH H O Me Me Me OH Et Et OH H Me The conformation of these structures are strongly influenced by the acyclic stereocenters Alborixin R = Me; X-206 R = H O O O O OH Me Me Me OH Me Me O C Me OH OH OH O O Et OH Me H Me OH Me Me H R Internal H-Bonding The conformation of these structures are strongly influenced by the acyclic stereocenters and internal H-bonding O O O O OH Me Me Me OH Me Me O C Me O OH OH O O Et OH Me H Me OH Me Me H R Metal ion ligation sites (M = Ag, K) M Synthesis: Evans, Bender, Morris, JACS 1988, 110, 2506

D. A. Evans Conformational Analysis: lonophore X-206/X-rays Chem 206 X-ray of lonophore X-206. H2O X-ray of lonophore X-206-Agt-Complex Internal H-Bonding Metal ion ligation sites(M= Ag, K)

D. A. Evans Chem 206 O O O O OH Me Me Me OH Me Me O C Me OH OH OH O O Et OH Me H Me OH Me Me H Internal H-Bonding O O O O OH Me Me Me OH Me Me O C Me O OH OH O O Et OH Me H Me OH Me Me H R Metal ion ligation sites (M = Ag, K) M Conformational Analysis: Ionophore X-206/X-rays X-ray of Ionophore X-206 × H2O X-ray of Ionophore X-206 - Ag+ - Complex

D. A. Evans Conformational Analysis: lonophore X-206/X-ray overlay Chem 206

D. A. Evans Conformational Analysis: Ionophore X-206/X-ray overlay Chem 206