D. A. Evans Rules for Ring Closure: Introduction Chem 206 Useful Literature Reviews http://www.courses.fasharvardedu/-chem206/ Johnson, C D (1993). " Stereoelectronic effects in the formation of 5- and 6-membered rings: the role of Baldwin's rules Acc. chem. Res. 26: 476-82 Beak, P (1992). " Determinations of transition-state geometries by the endocyclic restriction test: mechanisms of substitution at Chemistry 206 nonstereogenic atoms. Acc. Chem. Res 25: 215 Advanced organic Chemistry The Primary Literature Idwin, Chem. Soc. Chem. Comm. 1976. 734. 736 aldwin J. Chem. Soc. Chem. Comm. 1977 323 Baldwin, J. Org Chem 1977, 42, 3846 Lecture number 3 Baldwin, Tetrahedron 1982. 38 2939 Stereoelectronic Effects-2 Rules for Ring Closure: Baldwin's Rules i Problems of the Day Propose mechanisms for the following reactions Kirby, "Stereoelectronic Effects"Chapters 4, 5 NH2-NH Matthew d shair September 23, 2002
D. A. Evans Chem 206 Useful LIterature Reviews ■ Problems of the Day Chemistry 206 Advanced Organic Chemistry Lecture Number 3 Stereoelectronic Effects-2 Matthew D. Shair Monday, September 23, 2002 http://www.courses.fas.harvard.edu/~chem206/ Rules for Ring Closure: Introduction Johnson, C. D. (1993). “Stereoelectronic effects in the formation of 5- and 6-membered rings: the role of Baldwin's rules.” Acc. Chem. Res. 26: 476-82. Beak, P. (1992). “Determinations of transition-state geometries by the endocyclic restriction test: mechanisms of substitution at nonstereogenic atoms.” Acc. Chem. Res. 25: 215. The Primary Literature "Rules for Ring Closure: Baldwin's Rules" Propose mechanisms for the following reactions O O R R HO HO O R R + H + Baldwin, J. Chem. Soc., Chem. Comm. 1976, 734, 736. Baldwin, J. Chem. Soc., Chem. Comm. 1977 323. Baldwin, J. Org. Chem. 1977, 42, 3846. Baldwin, Tetrahedron 1982, 38, 2939. Me OMe O NH2–NH2 HN NH Me O Kirby, "Stereoelectronic Effects" Chapters 4, 5
D. A. Evans.J. Johnson Rules for Ring closure: Introduction Chem 206 Ring Closure and Stereoelectronic Considerations C. Nucleophilic ring closures sub-classified according to hybridization An Examination of baldwin's rules (tetrahedral tet; trigonal trig; digonal dig) "Baldwin,'s Rules"provides a qualitative set of generalizations on the D. Nucleophilic ring closures further subclassified according to size of obability of a given ring closure the fomed ring. For example There are circumstances where the"rules"don't apply a They do not apply to non-first-row elements participating in the 5-exo-t cyclization event. The longer bond lengths and larger atomic radii of 2nd row elements result in relaxed geometrical constraints For example, a change in a heteroatom fromo to S could result in relaxation of a given geometric constraint. X=O VS S u The" rules"do not apply to electrocyclic processes Nomenclature Required trajectories Classes of Ring Closing Processes A. EXo-cyclization modes identified by the breaking bond ing positioned exocyclic to the forming cycle 把“4 B. Endo-cyclization modes identified by the breaking bond being positioned endocyclic to the forming cycle X=first-row element N. O Baldwin. J. Chem. Soc. Chem. Commun. 1976. 734
D. A. Evans, J. Johnson Rules for Ring Closure: Introduction Chem 206 Ring Closure and Stereoelectronic Connsiderations An Examination of Baldwin's Rules "Baldwin's Rules" provides a qualitative set of generalizations on the probability of a given ring closure. There are circumstances where the "rules" don't apply. ■ They do not apply to non-first-row elements participating in the cyclization event. The longer bond lengths and larger atomic radii of 2nd row elements result in relaxed geometrical constraints. For example, a change in a heteroatom from O to S could result in relaxation of a given geometric constraint. Nomenclature Classes of Ring Closing Processes Y Y – Y Y – exo endo X X X X A. Exo-cyclization modes identified by the breaking bond being positioned exocyclic to the forming cycle. B. Endo-cyclization modes identified by the breaking bond being positioned endocyclic to the forming cycle. X = first-row element N, O C. Nucleophilic ring closures sub-classified according to hybridization state of electrophilic component: (tetrahedral = tet; trigonal = trig; digonal = dig) D. Nucleophilic ring closures further subclassified according to size of the fomed ring. For example: X – Y X Y – X – Y X Y – X – Y X Y – 5-exo-trig 5-exo-dig 5-exo-tet X Y X Y Y X Y X X Y X Y Baldwin, J. Chem. Soc., Chem. Commun., 1976, 734. ■ The "rules" do not apply to electrocyclic processes. Y Y - endo X •• X X = O vs S •• •• Required trajectories: a a a a a a * * a a
D A. Evans, J. Johnson Rules for Ring Closure: SP3 Carbon Related Systems Chem 206 Tetrahedral Carbon FURST-PLATTNER RULE In this simple model, the transition-state leading to 1 involves the All exo cyclization modes are allowed: n-exo-tet, n=3-) diaxial orientation of nucleophile and leaving group. This orientation affords the best overlap of the anti-bonding C-Y orbital and the nonbonding electron pairs on the nucleophile O In the formation of the diastereomeric epoxide 2, the proper alignment of orbitals may only be achieved by cyclization through the There are stereoelectronic issues to consider for n-exo-tet cyclizations "allowed", there are large rate differences the the rates of ring closure Formation of 3-Membered Rings (3-exo-tet) While the FURST-PLATTNER RULE deals wilth the microscopic H reverse, in the opening of epoxides by nucleophiles, the XCH2+Y stereoelectronic arguments are the same H2 Stereoelectronic Effects in Epoxide Ring Cleavage Conformational Effects in Epoxide Ring Formation/cleavage t e3C fuence ring formation. at operate in ring cleavage also formation. Consider a rigid cyclohexene oxide system 丰 √ faster 8-d slower < chair The diaxial nucleophilic ring cleavage of epoxides For more information on epoxide cleavage see handout 03A
D. A. Evans, J. Johnson Rules for Ring Closure: SP3 Carbon & Related Systems Chem 206 Tetrahedral Carbon All exo cyclization modes are allowed: (n-exo-tet, n = 3 ) Y C C Y – exo X X There are stereoelectronic issues to consider for n-exo-tet cyclizations Formation of 3-Membered Rings (3-exo-tet) X C H2 X CH2 C H2 C Y C H2 C H H X Y + Y– ‡ Conformational Effects in Epoxide Ring Formation/cleavage O H H Y O – Y O – H H H H Those stereoelectronic effects that operate in ring cleavage also influence ring formation. Consider a rigid cyclohexene oxide system: O H H O H Y d – d – ‡ O Y ‡ d – d – faster slower In this simple model, the transition-state leading to 1 involves the diaxial orientation of nucleophile and leaving group. This orientation affords the best overlap of the anti-bonding C–Y orbital and the nonbonding electron pairs on the nucleophile O– . In the formation of the diastereomeric epoxide 2, the proper alignment of orbitals may only be achieved by cyclization through the less-favored boat conformer. Accordingly, while both cyclizations are "allowed", there are large rate differences the the rates of ring closure. While the FÜRST-PLATTNER RULE deals wilth the microscopic reverse, in the opening of epoxides by nucleophiles, the stereoelectronic arguments are the same. 1 chair boat 2 Stereoelectronic Effects in Epoxide Ring Cleavage Me3C H O Nu- Me3C H HO Nu Me3C H O Nu- Me3C H Nu HO "The diaxial nucleophilic ring cleavage of epoxides" For more information on epoxide cleavage see Handout 03A. H H H H O Me H H Me HO Nu NuFÜRST-PLATTNER RULE •• •• H H
D A Evans, J.Johnson Rules for Ring Closure: SP3 Carbon Related Systems Chem 206 Tetrahedral Carbon Case 2: King, J.C.S. Chem. Comm, 1979, 1140 Endo cyclization modes that are disallowed ( n-endo-tet n=3→9) 8-endo-tet disfavored intermolecular endo X 8-endo-tet RXn exclusively The stereoelectronic requirement for a 180% X-C-Y bond angle is only met when the endo cyclization ring size reaches 9 or 10 members 9-endo-tet Case 1: Eschenmoser. Helvetica Chim Acta 1970. 53. 2059 SOzOMe borderline Conclusions 6-endo-tet disfavored Allowed endo cyclization modes will require transition state ring sizes of at least nine members Rxn excl i Intramolecular epoxidation has also been evaluated 8-endo-tet yclization exclusively intermolecular. However the exocyclic analog i disfavored n= 1: rXn exclusively intermolecular 6-exo-tet 0=s=0 Beak states that the conclusions made with carbol substitution also hold for oxygen atom transfer Rxn exclusively Beak, P(1992). Determinations of transition-state geometries by the endocyclic restriction test: mechanisms of substitution at nonstereogenic atoms ."Acc. chem. Res. 25: 215
D. A. Evans, J. Johnson Rules for Ring Closure: SP3 Carbon & Related Systems Chem 206 Tetrahedral Carbon Endo cyclization modes that are disallowed (n-endo-tet, n = 3 9) C Y endo X X Y C(SP3 ) The stereoelectronic requirement for a 180° X–C–Y bond angle is only met when the endo cyclization ring size reaches 9 or 10 members. CX3 O S O O O S O CY3 CX3 O- S O O O S O CY3 Cyclization exclusively intermolecular. However the exocyclic analog is exclusively intramolecular NaH 6-endo-tet disfavored CX2 I O S O O O S O CY3 CX2 O- S O O O S O CY3 NaH 6-exo-tet favored Case 1: Eschenmoser, Helvetica Chim. Acta 1970, 53, 2059. Case 2: King, J.C.S. Chem. Comm., 1979, 1140. NMe2 Me O S O O NMe3 + O S O O _ 8-endo-tet disfavored Rxn exclusively intermolecular (lecture 2) Rxn exclusively intramolecular Rxn exclusively intermolecular NMe2 SO2OMe NMe3 + SO3 – 8-endo-tet disfavored Rxn exclusively intermolecular NMe2 SO2OMe NMe3 + SO3 – 84% intermolecular, 16% intramolecular 9-endo-tet borderline Conclusions Allowed endo cyclization modes will require transition state ring sizes of at least nine members. Cl O–OH O Cl CO2H O n n Intramolecular epoxidation has also been evaluated Beak, JACS 1991, 113, 6281. n = 1: rxn exclusively intermolecular n = 9: rxn is intramolecular 8-endo-tet disfavored Beak states that the conclusions made with carbon substitution also hold for oxygen atom transfer. •• •• Beak, P. (1992). “Determinations of transition-state geometries by the endocyclic restriction test: mechanisms of substitution at nonstereogenic atoms.” Acc. Chem. Res. 25: 215
D A Evans,J. Johnson Rules for Ring closure: SP2 Carbon Related Systems Chem 206 Trigonal Carb Endo cyclization modes that are disallowed (3 to 5-endo-trig) n-endo-tng X= first-row element The 5-endo-trig cyclization is a watershed case distance from reacting centers: 2.77A Case 1: Baldwin. J. Chem. Soc. Chem. Commun., 1976. 734 CO,Me base It is possible that a"nonvertical 5-endo-trig trajectory is operational like that suspected in C=o addition however cO, Me base COmE Second row atom relaxes the cyclization geometrical requirement Case 2: Baldwin. J. chem. Soc. Chem. Commun. 1976 736 CO,Me MeO2C 5-exo-trig
D. A. Evans, J. Johnson Rules for Ring Closure: SP2 Carbon & Related Systems Chem 206 Trigonal Carbon Endo cyclization modes that are disallowed (3 to 5-endo-trig) n-endo-trig The 5-endo-trig cyclization is a watershed case X = first-row element Case 1: Baldwin, J. Chem. Soc., Chem. Commun., 1976, 734. OH CO2Me O CO2Me 5-endo-trig Disfavored base X however SH CO2Me S base CO2Me X Second row atom relaxes the cyclization geometrical requirement Case 2: Baldwin, J. Chem. Soc., Chem. Commun., 1976, 736. NH2 MeO2C CO2Me HN HN MeO2C MeO2C CO2Me O 5-endo-trig 0% 5-exo-trig 100% NH2 MeO2C CO2Me distance from reacting centers: 2.77 Å It is possible that a "nonvertical" trajectory is operational like that suspected in C=O addition Y C Y – C X •• X