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Các quy tắc của Baldwin trong hóa học hữu cơ là một loạt các hướng dẫn nêu ra những ưu điểm tương đối của phản ứng đóng vòng trong các hợp chất béo . Chúng được đề xuất lần đầu tiên bởi Jack Baldwin vào năm 1976. 1 2 Các quy tắc của Baldwin thảo luận về tỷ lệ đóng vòng tương đối của các loại khác nhau này. Những thuật ngữ này không nhằm mô tả xác suất tuyệt đối mà một phản ứng sẽ xảy ra hoặc không xảy ra, mà chúng được sử dụng theo nghĩa tương đối. Một phản ứng không được ưa chuộng (chậm) không có tỷ lệ cạnh tranh hiệu quả với một phản ứng thay thế được ưa chuộng (nhanh). Tuy nhiên, sản phẩm bị biến dạng có thể được quan sát thấy nếu không có phản ứng thay thế nào được ưu tiên hơn. Các quy tắc phân loại việc đóng vòng theo ba cách: số nguyên tử trong vòng mới hình thành thành các vòng đóng exo và end , tùy thuộc vào việc liên kết bị phá vỡ trong quá trình đóng vòng là bên trong ( endo ) hay bên ngoài ( exo ) vòng đang được hình thành thành hình học tet , trig và dig của nguyên tử bị tấn công, tùy thuộc vào việc carbon điện di này là tứ diện ( lai sp 3 ), lượng giác ( lai sp 2 ) hay chéo ( lai sp ). Do đó, phản ứng đóng vòng có thể được phân loại thành phản ứng, ví dụ, 5 extrig .
D A Evans Rules for Ring Closure: Introduction Chem 206 The Primary Literature http://www.courses.fas.harvard.edu/~chem206/ Baldwin, J Chem Soc., Chem Comm 1976, 734, 736 Baldwin, J Chem Soc., Chem Comm 1977 233 Baldwin, J Org Chem 1977, 42, 3846 Baldwin, Tetrahedron 1982, 38, 2939 Chemistry 206 Advanced Organic Chemistry Lecture Number Stereoelectronic Effects-3 "Rules for Ring Closure: Baldwin's Rules" Kirby, "Stereoelectronic Effects" Chapters 4, Useful LIterature Reviews Johnson, C D (1993) “Stereoelectronic effects in the formation of 5and 6-membered rings: the role of Baldwin's rules.” Acc Chem Res 26: 476-82 (Handout) Beak, P (1992) “Determinations of transition-state geometries by the endocyclic restriction test: mechanisms of substitution at nonstereogenic atoms.” Acc Chem Res 25: 215 (Handout) ■ Problems of the Day Propose mechanisms for the following reactions HO R O + HO R D A Evans Friday, September 19, 2003 O OMe R O R O HN NH NH2–NH2 Me 3-00-Cover Page 9/19/03 8:36 AM H+ Me O D A Evans, J Johnson Chem 206 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 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: There are circumstances where the "rules" don't apply ■ They 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 5-exo-tet X Y X Y– 5-exo-trig For example, a change in a heteroatom from O to S could result in relaxation of a given geometric constraint X X Y Y– endo X = O vs S •• X Y X 5-exo-dig Y X X Y– Y ■ The "rules" not apply to electrocyclic processes Required trajectories (Baldwin): Nomenclature Classes of Ring Closing Processes A Exo-cyclization modes identified by the breaking bond being positioned exocyclic to the forming cycle exo X X X •• •• 3-01-Baldwin Rules-1 9/18/03 3:38 PM = 109 Y X * endo Y X Y X = first-row element N, O Y X X X Y Y B Endo-cyclization modes identified by the breaking bond being positioned endocyclic to the forming cycle X = 180 Y Y 120 * Y Will come back to this case later X Y Baldwin, J Chem Soc., Chem Commun., 1976, 734 Rules for Ring Closure: SP3 Carbon & Related Systems D A Evans, J Johnson FÜRST-PLATTNER RULE Tetrahedral Carbon All exo cyclization modes are allowed: (n-exo-tet, n = ) •• exo X C C X Y Chem 206 Y– There are stereoelectronic issues to consider for n-exo-tet cyclizations In this simple model, the transition-state leading to 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 Formation of 3-Membered Rings (3-exo-tet) H H •• C X ‡ H Y C H2 C X X Y H C H2 CH2 + Y– C H2 While the FÜRST-PLATTNER RULE deals wilth the microscopic reverse, in the opening of epoxides by nucleophiles, the stereoelectronic arguments are the same Stereoelectronic Effects in Epoxide Ring Cleavage Nu Conformational Effects in Epoxide Ring Formation/cleavage - Nu Me3C Those stereoelectronic effects that operate in ring cleavage also influence ring formation Consider a rigid cyclohexene oxide system: Y Y δ– H H H chair boat 3-02-Baldwin Rules-2 9/18/03 3:39 PM O δ– Nu- Nu H Nu Me O Y H H H Me slower Me3C H O Y δ– ‡ O– HO HO Nu Me3C H δ O H H H - – O– H O H H Me3C H ‡ faster H O O H HO H "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 Tetrahedral Carbon Case 2: King, J.C.S Chem Comm., 1979, 1140 O Endo cyclization modes that are disallowed (n-endo-tet, n = 9) O O 8-endo-tet disfavored S O Me NMe2 Y C(SP3) C •• •• X Y SO2OMe NMe2 The stereoelectronic requirement for a 180° X–C–Y bond angle is only met when the endo cyclization ring size reaches or 10 members SO2OMe Case 1: Eschenmoser, Helvetica Chim Acta 1970, 53, 2059 O O O S S O CX3 O S O NaH 6-endo-tet disfavored NMe2 O Rxn exclusively intermolecular (lecture 2) S O O O O S O NaH 6-exo-tet favored 3-03-Baldwin Rules-3 9/18/03 4:07 PM NMe3+ Rxn exclusively intermolecular SO3– 9-endo-tet borderline NMe3+ O CX2 O S CY3 Beak, JACS 1991, 113, 6281 Cl O–OH 8-endo-tet disfavored Cl n - Rxn exclusively intramolecular CY3 SO3– O O S O CX2I 8-endo-tet disfavored Allowed endo cyclization modes will require transition state ring sizes of at least nine members CY3 Cyclization exclusively intermolecular However the exocyclic analog is exclusively intramolecular S NMe3+ Intramolecular epoxidation has also been evaluated CY3 O _ Conclusions CX3 O O 84% intermolecular, 16% intramolecular O- O S Rxn exclusively intermolecular endo X Chem 206 O CO2H n O n = 1: rxn exclusively intermolecular n = 9: rxn is intramolecular 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 Rules for Ring Closure: SP2 Carbon & Related Systems D A Evans, J Johnson Trigonal Carbon Endo cyclization modes that are disallowed (3 to 5-endo-trig) MeO2C CO2Me NH2 n-endo-trig X •• Y X C C Y– X = first-row element The 5-endo-trig cyclization is a watershed case distance from reacting centers: 2.77 Å Case 1: Baldwin, J Chem Soc., Chem Commun., 1976, 734 CO2Me base CO2Me It is possible that a "nonvertical" trajectory is operational like that suspected in C=O addition X OH 5-endo-trig Disfavored however CO2Me O CO2Me base S SH Second row atom relaxes the cyclization geometrical requirement Case 2: Baldwin, J Chem Soc., Chem Commun., 1976, 736 MeO2C MeO2C CO2Me X NH2 CO2Me HN 5-endo-trig 0% MeO2C HN O 3-04-Baldwin Rules-4 9/18/03 4:07 PM 5-exo-trig 100% Chem 206 D A Evans, J Johnson Rules for Ring Closure: SP2 Carbon & Related Systems Case 2: continued MeO2C Apparent exceptions to disallowed 5-endo-trig cyclization process MeO2C CO2Me CO2Me X NH2 O HN N 5-endo-trig 0% + N CH3CO2H 5-exo-trig 100% HN O CO2Me R HC N CO2Me KOtBu Control experiment: Intermolecular reaction favors conjugate addtion CO2Me Me Me H N Ph CO2Me H N O 100% Ph R2 R1 HN Ph O Ph OK NH2NH2 OMe 65 oC 1) EtO2CCl, pyridine 2) NH2NH2 Ph HN NH Ph H2N X R R R NH 5-endo-trig CO2Me R2 HO (CH2OH)2 O R R O MeI 200 oC (CH2OH)2 R O HN 3:1 Grigg, J Chem Soc., Chem Commun 1980, 648 Does the illustrated ketalization process necessarily violate "the rules"? O R2 CO2Me R1 = aryl, R2 = aryl, alkyl 0% Case 3: O O CO2Me R1 CO2Me PhCH2NH2 N OH Filer, J Am Chem Soc 1979, 44, 285 MeO2C Me Chem 206 O OH ( )2 H+ H+ R H+ O R O OH R –H2O R O + ( )2 5-endo-trig disfavored ? O Ph OMe R Ph CO2Me NH2NH2 65 oC HN NH2 3-05-Baldwin Rules-5 9/18/03 4:08 PM Ph 5-exo-trig O HN + HO R O OH 5-exo-tet ( )2 favored ? R O R O NH 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 D A Evans, J Johnson Rules for Ring Closure: SP2 Carbon & Related Systems More Exceptions Chem 206 Bu Zard, Org Lett 2002, 4, 1135 O MeO S N OEt NaH Y O DMF, 60 °C HO Y O N S ROOR heat O 80% O O MeO O MeO O MeO Bu X MeO X Y Cond Yield F F DMF, 60 °C, h 80 F H DMF, 80 °C, 43 h 17 Cl Cl DMF, 60 °C, h –– Br Br DMF, 60 °C, h 15 O N MeO N 5-endo-trig Ichikawa, et al Synthesis 2002, 1917-1936, PDF on Course Website Numerous other cases are provided in this review O Br O O O H O O Revisiting Case with Fluorines O Bu3SnH O AIBN O MeO2C MeO2C H N 82% Ts O 5-exo-trig OMe TsHN MeO2C 5-endo-trig Favored CO2Me N Ts Not Observed H O O 5-endo-trig O O O CF2 MeO2C MeO2C N Ts Chem Comm 2088, 28 Review: "5-Endo-Trig Radical Cyclizatons" Ishibashi, et al Synthesis 2002, 695-713, PDF on Course Website 3-06-Baldwin Rules-6 9/18/03 5:10 PM O Not Observed 5-exo-trig TsHN OMe CF2 MeO2C 5-endo-trig CO2Me N Ts F Favored Rules for Ring Closure: SP2 Carbon & Related Systems D A Evans, J Johnson Chem 206 Trigonal Carbon: Exocyclic Enolate Alkylation distance between reacting centers: 3.37Å exo – C O C C C C O Y Y- C Br X ■ By definition, an exo-tet cyclization, but stereoelectronically behaves as an endo trig Me Me O (1) Me X MO O only observed product distance between reacting centers: 3.04Å However: Me The relaxed geometrical constraint provided by the added CH2 group now renders the 6-membered cyclization possible Me KOt-Bu or LDA Me O Me O The overlap for C-alkylation is poor due to geometrical constraints of 5-membered ring Me Br Me Me MO Br Me > 95% by NMR O Baldwin, J Chem Soc., Chem Commun 1977, 233 ■ Given the failure of the enolate alkylation shown above (eq 1), explain why these two cyclizations are successful MO Br O Br base NHAr N O O R O Ar R NH Ar R Favorskii Rearrangement (Carey, Pt B, pp 609-610) Your thoughts on the mechanism R base OMs 3-07-Baldwin Rules-7 9/18/03 4:09 PM O O O Cl MeO– N Ar –HCl CO2Me MeO– D A Evans, J Johnson Rules for Ring Closure: SP2 & SP Carbon & Related Systems Trigonal Carbon: Intramolecular Aldol Condensations Chem 206 Digonal Carbon: Cyclizations on to Acetylenes Baldwin, Tetrahedron 1982, 38, 2939 DIGONAL: Angle of approach for attack on triple bonds (Enolendo)-Exo-trig X MO R Y R Baldwin: Nu- X O YM 120° Favored: 6-7-(enolendo)-exo-trig Disfavored: 3-5-(enolendo)-exo-trig - and 4-Exo-dig are disfavored - to 7-Exo-dig are favored - to 7-Endo-dig are favored 120° E+ (Enolexo)-exo-trig X X O MO R Y Ab initio SCF 4-31G calculations for the interaction of hydride with acetylene: YM R H Favored: 3-7-(enolexo)-exo-trig _ H 127 o 2.13 H O 5-(Enolendo)-Exo-trig Me Me H C H 156o 1.22 6-(Enolendo)-Exo-trig Me O H Me Me Me O Me O Houk, J.ACS.1979, 101, 1340 H Me STO-3G minimal basis set 110o -120o 1.5-2.0 favored Me 4-31G basis set C O O I 148o H C C Dunitz, Helv Chim Acta 1978, 61, 2538 H O III Crystal Structures not support Baldwin O II O Statistical Distribution, (I + II)/III = 2:1 Experimental Distribution, = 0:100 N N (KOH, MeOH, r.t., min, 77% y.) O- N 2.92 + O + 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 N 104o 2.44 93o N 86o N J Dunitz and J Wallis J C S Chem Comm 1984, 671 3-08-Baldwin Rules-8 9/18/03 5:49 PM Rules for Ring Closure: SP Carbon & Related Systems D A Evans, J Johnson Endo Digonal versus Endo Trigonal Cyclizations Chem 206 ■ Indole synthesis: CH3 5-endo-trig + N C- CH2R equiv LDA equiv RX -78 oC + N C- R = Me, Bu, CO2Me Y LiTMP X: In-plane approach; nucleophile lone pair is orthogonal to π* R Out-of-plane approach; nucleophile lone pair can't achieve Bürgi-Dunitz angle Saegusa, J Am Chem Soc 1977, 99, 3532 N Li O HO n X Me NaOMe MeOH Ph Magnus, J Am Chem Soc 1978, 100, 7746 Me Me O 5-endo-dig Ph 5-exo-dig O R OH O NaOMe X Li R 5-endo-trig O Ph Ph however, the acid catalyzed version does cyclize 4-endo-dig 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 3-09-Baldwin Rules-9 9/19/03 8:38 AM Li Ph R = H, OMe Li X Li OMe n Developing negative charge on the central allenic carbon is in the same plane as the OMe group O O O KOtBu n n = 1,2 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 Me OMe MeO Allowed due to in-plane pi orbitals Y HO Li+ ■ Spiro dihydrofuranones: 5-endo-dig :X _ Ph Rules for Ring Closure: SP Carbon & Related Systems D A Evans, J Johnson Chem 206 Digonal Cyclizations: Interesting Examples Et3N, Toluene, reflux 12 h, 65-70% y MeO2C ■ Trost, J Am Chem Soc., 1979, 101, 1284 CN Proposes E-olefin geometry, E/Z > 95:5 CN O O R CO2Me R' : 5-exo-dig 30-40 kcal/mol O HO2C H Conclusions and Caveats Hirsutic Acid C OTBS LiCH2NC; TBS-Cl OTBS 1) RCOCl 2) AgBF4 71% Me Me + N : R' ? OH H O R Me N+ 86% C R CO Works for varying ring sizes and R groups; acylnitrilium ion can also work as an electophile in a Friedel-Crafts type of reaction 5-endo-dig ■ Baldwin's Rules are an effective first line of analysis in evaluating the stereoelectronics of a given ring closure ■ Baldwin's Rules have provided an important foundation for the study of reaction mechanism ■ 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" ■ Structural modifications can dramatically affect the cyclization mode; beware of imines and epoxides EXO ■ Livinghouse, Tetrahedron 1992, 48, 2209 Tet O H Me R N O 3-10-Baldwin Rules-10 9/18/03 5:21 PM Trig ENDO Dig X X Tet Trig X X X X X X Dig