哈佛大学高等有机.pdf

Chem 206 D A EvansAcyclic Conformational Analysis 1 D A Evans Monday September 26 2005 http www courses fas harvard edu chem206 Chemistry 206 Advanced Organic Chemistry Lecture Number 4 Baldwin s Rules 2 Conformational Analysis 1 Baldwin s Rules for Ring Closure Ethane Propane Butane Chapters 2 however it is well known by some that the rate determining step is dehydration in a base catalyzed aldol condensation Digonal Carbon Cyclizations on to Acetylenes DIGONAL Angle of approach for attack on triple bonds 3 and 4 Exo dig are disfavored 5 to 7 Exo dig are favored 3 to 7 Endo dig are favored Baldwin 120 120 E Nu Ab initio SCF 4 31G calculations for the interaction of hydride with acetylene J Dunitz and J Wallis J C S Chem Comm 1984 671 N N N O Crystal Structures do not support Baldwin HH CC H H H CC H HH 127 o 156o 148o 2 13 4 31G basis set Houk J ACS 1979 101 1340 1 22 110o 120o 1 5 2 0 STO 3G minimal basis set Dunitz Helv Chim Acta 1978 61 2538 N NO N 104o 93o 2 44 2 92 86o H Chem 206 D A Evans J JohnsonRules for Ring Closure SP Carbon nucleophile lone pair is Out of plane approach nucleophile lone pair can t achieve B rgi Dunitz angle X Y orthogonal to Y X Allowed due to in plane pi orbitals For an opposing viewpoint to Baldwin s view of nucleophile trajectories see Menger s article on directionality in solution organic chemistry Tetrahedron 1983 39 1013 5 endo dig X OH O R O O R 5 endo trig R H OMe 5 endo dig HO O Ph Me Me O Me Me Ph O NaOMe MeOH however the acid catalyzed version does cyclize Baldwin J Chem Soc Chem Commun 1976 736 Johnson Can J Chem 1990 68 1780 J Am Chem Soc 1983 105 5090 J Chem Soc Chem Commun 1982 36 X NaOMe CH3 N C CH2R N C N R 2 equiv LDA 2 equiv RX 78 oC R Me Bu CO2Me LiTMP Saegusa J Am Chem Soc 1977 99 3532 Indole synthesis Li O HO OMe O OMe Spiro dihydrofuranones n n Li MeO n KOtBu Developing negative charge on the central allenic carbon is in the same plane as the OMe group Magnus J Am Chem Soc 1978 100 7746 n 1 2 4 endo dig 5 exo dig Li Ph PhLi Li Ph Li Ph X Chem 206 D A Evans J JohnsonRules for Ring Closure SP Carbon beware of imines and epoxides EXO TetTrigDig ENDO 3 4 5 6 7 DigTrigTet X X X X X X X X X X O Me OTBS Me N C OTBS Me N C O R N O O R HMe LiCH2NC TBS Cl 71 1 RCOCl 2 AgBF4 86 Livinghouse Tetrahedron 1992 48 2209 5 endo dig Works for varying ring sizes and R groups acylnitrilium ion can also work as an electophile in a Friedel Crafts type of reaction O CN MeO2C OCO2Me CN O OH HO2C H H 5 exo dig Et3N Toluene reflux 12 h 65 70 y Trost JACS 1979 101 1284 Hirsutic Acid C Digonal Cyclizations Interesting Examples Chem 206D A EvansAcyclic Conformational Analysis 1 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 E kcal mol 1 Eclipsed atomsStructure For purposes of analysis each eclipsed conformer may be broken up into its component destabilizing interactions Ethane Rotational Barrier The FMO View 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 F Weinhold Angew nature 2001 411 539 541 A New Twist on Molecular Shape C H LUMO C H HOMO In the staggered conformation there are 3 anti periplanar C H Bonds C H HOMO C H LUMO C H C H In the eclipsed conformation there are 3 syn periplanar C H Bonds C H C H CC CC C H C H CC HH HH H H Following this argument one might conclude that Me Me Me 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 Calculate the the rotational barrier about the C1 C2 bond in isobutane Chem 206D A EvansAcyclic Conformational Analysis Butane The 1 2 Dihaloethanes X Cl H 0 9 1 3 kcal mol X Br H 1 4 1 8 kcal mol X F H 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 HH H H C X H HH X Discuss with class the origin of the gauche stabilization of the difluoro anaolg Recent Article Chem Commun 2002 1226 1227 handout G 2 3RT Log10K G RT Ln K Relationship between G and Keq and pKa Recall that or G 298 1 4 Log10Keq At 298 K 2 3RT 1 4 G in kcal Mol 1 G 298 1 4 pKeq pKeq Log10KeqSince pKeq 0 1 2 0 1 4 1 0 10 100 G Keq 2 8 kcal mol Hence pK is proportional to the free energy change E eclipsed conformation staggered conformation Using the eclipsing interactions extracted from propane X 206 R H OOOO OH Me Me Me OH MeMe O C Me OH OH OH O O Et OH Me H Me OH Me Me H R Internal H Bonding OOOO OH Me Me Me OH MeMe 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 D A EvansChem 206Conformational Analysis Ionophore X 206 X rays OOOO OH Me Me Me OH MeMe O C Me OH OH OH O O Et OH Me H Me OH Me Me H Internal H Bonding X ray of Ionophore X 206 H2O The Total Synthesis of the Polyether Antibiotic X 206 Evans D A Bender S L Morris J J Am Chem Soc 1988 110 2506 2526 OOOO OH Me Me Me OH MeMe 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 X ray of Ionophore X 206 Ag Complex Stabilized Eclipsed Conformations in Simple OlefinsD A EvansChem 206 Simple olefins exhibit unusal conformational properties relative to their saturated counterpa