Chem 206D. A. Evans Useful LIterature Reviews a73 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 HOO 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 Chem 206D. A. Evans, J. Johnson Rules for Ring Closure: Introduction 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. a73 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 XX 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 elementN, 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 YX YX Y X YX X Y X Y Baldwin, J. Chem. Soc., Chem. Commun., 1976, 734. a73 The "rules" do not apply to electrocyclic processes. Y Y-endoX X??X = O vs S ?? ?? Required trajectories: α α α α α α α α* * Chem 206D. A. Evans, J. Johnson Rules for Ring Closure: SP3 Carbon & Related Systems Tetrahedral Carbon All exo cyclization modes are allowed: (n-exo-tet, n = 3 ) YC C Y – exo XX There are stereoelectronic issues to consider for n-exo-tet cyclizations Formation of 3-Membered Rings (3-exo-tet) X CH2 CH2X C H2 C Y CH2 C H H YX + Y– ? Conformational Effects in Epoxide Ring Formation/cleavage O HH Y O – Y O –H H H H Those stereoelectronic effects that operate in ring cleavage alsoinfluence ring formation. Consider a rigid cyclohexene oxide system: O H H O H Y δ– δ– ? O Y ? δ– δ– 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 2chair boat 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. HH HH O Me H H Me HO NuNu- FüRST-PLATTNER RULE ?? ?? H H Chem 206D. A. Evans, J. Johnson Rules for Ring Closure: SP3 Carbon & Related Systems Tetrahedral Carbon Endo cyclization modes that are disallowed(n-endo-tet, n = 3 9) C Y endoX YXC(SP 3)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. CX3O SO O S OO CY3 CX3O -S O O S OO CY3 Cyclization exclusively intermolecular. However the exocyclic analog is exclusively intramolecular NaH 6-endo-tetdisfavored CX2IO SO O S OO CY3 CX2 O-S O O S OO CY3 NaH6-exo-tet favored Case 1: Eschenmoser, Helvetica Chim. Acta 1970, 53, 2059. Case 2: King, J.C.S. Chem. Comm., 1979, 1140. NMe2Me OS O O NMe3+ OS O O _8-endo-tetdisfavored Rxn exclusively intermolecular (lecture 2) Rxn exclusively intramolecular Rxn exclusively intermolecular NMe2 SO2OMe NMe 3+ SO3–8-endo-tetdisfavored Rxn exclusively intermolecular NMe2 SO2OMe NMe3+ SO3– 84% intermolecular, 16% intramolecular 9-endo-tetborderline Conclusions Allowed endo cyclization modes will require transition state ring sizesof at least nine members. Cl O–OHO Cl CO2H On n Intramolecular epoxidation has also been evaluatedBeak, JACS 1991, 113, 6281. n = 1: rxn exclusively intermolecularn = 9: rxn is intramolecular 8-endo-tetdisfavored 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. Chem 206D. A. Evans, J. Johnson Rules for Ring Closure: SP2 Carbon & Related Systems 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-trigDisfavored baseX however SH CO2Me S CO2Mebase X Second row atom relaxes the cyclization geometrical requirement Case 2: Baldwin, J. Chem. Soc., Chem. Commun., 1976, 736. NH2 CO2MeMeO2C HN HN MeO2C MeO2C CO2Me O 5-endo-trig0% 5-exo-trig100% NH2 CO2MeMeO2C distance from reacting centers: 2.77 ? It is possible that a "nonvertical" trajectory is operational like that suspected in C=O addition YC Y –CX X?? Chem 206D. A. Evans, J. Johnson Rules for Ring Closure: SP2 Carbon & Related Systems XNH2 CO2MeMeO2C HN HN MeO2C MeO2C CO2Me O 5-endo-trig0% 5-exo-trig100% CO2Me Me Me CO2Me MeHNPh O HN Ph Ph OK O Ph OMe O Ph CO2Me HN NH2 HN NH O Ph Ph O NHH2N 100% Control experiment: Intermolecular reaction favors conjugate addtion. 1) EtO2CCl, pyridine2) NH 2NH2 5-exo-trig65 oC 200 oC 5-endo-trig 0% MeI X Apparent exceptions to disallowed 5-endo-trig cyclization process N O N OH N O NR1HC CO2Me R2 CO2Me HN CO2Me CO2Me R1 HN CO2MeR1 CO2MeR2 R2 Filer, J. Am. Chem. Soc. 1979, 44, 285. R1 = aryl, R2 = aryl, alkyl + KOtBu 3:1 Grigg, J. Chem. Soc., Chem. Commun. 1980, 648. R R O O R R O (CH2OH)2 H+ Does the illustrated ketalization process necessarily violate "the rules"? R R O (CH2OH)2 O OHRR HO H+ O OHRR HO+ H+ –H2O O OHRR + R R O O5-exo-tet 5-endo-trigdisfavored ? favored ? ( )2 ( )2 ( )2 Case 2: continued... Case 3: Ph OMe O 65 oC HN NH OPh 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. PhCH2NH2 NH2NH2 CH3CO2H NH2NH2 Chem 206D. A. Evans, J. Johnson Rules for Ring Closure: SP2 Carbon & Related Systems Trigonal Carbon: Exocyclic Enolate Alkylation Br MO MeMe Me Br MeMe O O MeMe a73 By definition, an exo-tet cyclization, but stereoelectronically behaves as an endo trig. KOt-Bu or LDA > 95% by NMR O Me MeO Me Me X YC Y- exo CCCOCC–O only observedproduct However: Baldwin, J. Chem. Soc., Chem. Commun. 1977, 233. NO R R Ar R OMs RO NHAr base NO ArbaseNHArO Br a73 Given the failure of the enolate alkylation shown above (eq 1),explain why these two cyclizations are successful. (1) Br MO OX The overlap for C-alkylation is poor due to geometrical constraints of 5-membered ring distance between reactingcenters: 3.04? distance between reacting centers: 3.37? BrMO O The relaxed geometrical constraint provided by the added CH2 group now renders the 6-membered cyclization possible Favorskii Rearrangement (Carey, Pt B, pp 609-610) Your thoughts on the mechanism ClO MeO– O CO2MeMeO– –HCl Chem 206D. A. Evans, J. Johnson Rules for Ring Closure: SP2 & SP Carbon & Related Systems Trigonal Carbon: Intramolecular Aldol Condensations RMO X Y RO X YM RMO X Y X YM RO OMe OMe OMe OMe Me O Me Me O O Me O Me O (Enolendo)-Exo-trig (Enolexo)-exo-trig Favored: 3-7-(enolexo)-exo-trig Favored: 6-7-(enolendo)-exo-trigDisfavored: 3-5-(enolendo)-exo-trig 5-(Enolendo)-Exo-trig 6-(Enolendo)-Exo-trig Statistical Distribution, (I + II)/III = 2:1Experimental Distribution, = 0:100 (KOH, MeOH, r.t., 5 min, 77% y.) Baldwin, Tetrahedron 1982, 38, 2939 favored Caution: Baldwin's conclusions assume that the RDS is ring closure; 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: 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 C CH H H C C H H H _ 127 o 156o 148o2.13 4-31G basis set Houk, J.ACS.1979, 101, 1340.1.22 110o -120o1.5-2.0 STO-3G minimal basis setDunitz, Helv Chim. Acta 1978, 61, 2538. N NO N104o 93o2.44 2.92 86o 120° 120° E+ Nu- I II III H Chem 206D. A. Evans, J. Johnson Rules for Ring Closure: SP Carbon & Related Systems Endo Digonal versus Endo Trigonal Cyclizations 5-endo-trig In-plane approach;nucleophile lone pair is Out-of-plane approach;nucleophile lone pair can'tachieve Bürgi-Dunitz angle X: Y orthogonal to pi* 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 OH O R OO R5-endo-trig R = H, OMe 5-endo-digHO O Ph MeMe O MeMe Ph O NaOMeMeOH however, the acid catalyzed version does cyclizeBaldwin, J. Chem. Soc., Chem. Commun., 1976, 736. Johnson, Can. J. Chem. 1990, 68, 1780J. Am. Chem. Soc. 1983, 105, 5090 J. Chem. Soc., Chem. Commun. 1982, 36. CH3 N+ C- CH2R N+ C- N R 2 equiv. LDA 2 equiv. RX -78 oC R = Me, Bu, CO2Me LiTMP O _ HO OMe O OMe Saegusa, J. Am. Chem. Soc. 1977, 99, 3532. a73 Indole synthesis: a73 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 Ph Li Li Ph Li PhX X X NaOMe Li+ Chem 206D. A. Evans, J. Johnson Rules for Ring Closure: SP Carbon & Related Systems O CN MeO2C O CO2Me CN R R' O OH HO2C H H O Me OTBS MeN+ C- OTBS Digonal Cyclizations: Interesting Examples N+ C 5-exo-dig Et3N, Toluene, reflux 12 h, 65-70% y. O R a73 Trost, J. Am. Chem. Soc., 1979, 101, 1284. Proposes E-olefin geometry, E/Z > 95:5 : N O O RH Me 30-40 kcal/mol ? Hirsutic Acid C LiCH2NC;TBS-Cl 71% 1) RCOCl2) AgBF 4 86% a73 Livinghouse, Tetrahedron 1992, 48, 2209. 5-endo-dig Works for varying ring sizes and R groups; acylnitriliumion can also work as an electophile in a Friedel-Crafts type of reaction R R' : Conclusions and Caveats a73 Baldwin's Rules are an effective first line of analysis in evaluating the stereoelectronics of a given ring closure a73 Baldwin's Rules have provided an important foundation for the study of reaction mechanism a73 Competition studies between different modes of cyclization only give information about relative rates, and are not an absolute indicator of whether a process is "favored" or "disfavored" a73 Structural modifications can dramatically affect the cyclization mode; beware of imines and epoxides EXO Tet Trig Dig ENDO 3 4 5 6 7 DigTrigTet X X X X X X X X