D.A. Evans Functional Group Classification Scheme for Polar Bond Constructions Chem 206 Papers of Historical Interest http://www.courses.fasharvard.edu/-chem206/ Arthur Lapworth: The Genesis of Reaction M. Saltzman chem Ed 1972. 49. 750 Chemistry 206 A Theoretical Derivation of the Principle of Induced Altemate Polarities. A. Lapworth J. Chem. Soc. 1922, 121, 416 Advanced Organic Chemistry " The Electron Theory of Valence as Applied to Organic Compounds J. Steiglitz J. Am. Chem. Soc. 1922, 44, 1293 Lecture number 26 Monographs Hase, T. A "Umpoled Synthons. A Survey of Sources and Uses in Synthesis Ambiphilic Functional Groups ohn Wiley Sons, Inc: New York, 1987. Nitro and Diazo Groups Ho, T.-L. "Polarity Control for Synthesis", John Wiley& Sons, Inc. New York, Historical Perspective Ono, N, "The Nitro Group in Organic Synthesis", Wiley-VCH, 2001 ■ Charge Affinity Patterns a Functional Group Classification Scheme Several Interesting Problems I The Chemistry of the -NO2 Group The Chemistry of the -N2 Group Provide a mechanism for the nef reaction R Reading Assignment for this Week: Nef Reaction 2)H3O An Organizational Scheme for the Classification of Functional Groups Applications to the Construction of Difunctional Relationships D A. Evans Unpublished manuscript (Lecture 26A, pdf) Cume Question: The von Richter reaction is illustrated in the accompanying equation. Methods of Reactivity Umpolung D Seebach Angew. Chem. Int Ed Engl. 1979, 18, 239 Please provide a plausible mechanism for this transformation taking into account the following observations. (a)If5N-labeled KCN is used, the N2 formed is half labeled: (b) Nitroaliphatic Compounds-ldeal Intermediates in Organic Synthesis"Seebach, 3-bromo-benzonitrile does not form 3-bromo-benzoic acid under the reaction conditions D.et.al,chma,1979,33,1-18 Synthetic Applications of a-Diazocarbonyl Compounds Krista Beaver, Evans Group Seminar (Lecture 26B, pdf) KCN Monday, Matthew d. shair November 18. 2002 aqueous EtoH CO2H
http://www.courses.fas.harvard.edu/~chem206/ Br NO2 KCN N R R O O H Br CO2H N2 O R R D. A. Evans Chem 206 Matthew D. Shair Monday, November 18, 2002 Reading Assignment for this Week: Functional Group Classification Scheme for Polar Bond Constructions Chemistry 206 Advanced Organic Chemistry Lecture Number 26 Ambiphilic Functional Groups-1 Nitro and Diazo Groups ■ Historical Perspective ■ Charge Affinity Patterns ■ Functional Group Classification Scheme ■ The Chemistry of the –NO2 Group ■ The Chemistry of the –N2 Group "An Organizational Scheme for the Classification of Functional Groups. Applications to the Construction of Difunctional Relationships." D. A. Evans Unpublished manuscript (Lecture 26A, pdf) "Methods of Reactivity Umpolung." D. Seebach Angew. Chem. Int. Ed. Engl. 1979, 18, 239. "Nitroaliphatic Compounds–Ideal Intermediates in Organic Synthesis"' Seebach, D. et. al, Chimia, 1979, 33, 1-18. "Synthetic Applications of a-Diazocarbonyl Compounds" Krista Beaver, Evans Group Seminar (Lecture 26B, pdf) "Arthur Lapworth: The Genesis of Reaction Mechanism." M. Saltzman J. Chem. Ed. 1972, 49, 750. "A Theoretical Derivation of the Principle of Induced Alternate Polarities." A. Lapworth J. Chem. Soc. 1922, 121, 416. "The Electron Theory of Valence as Applied to Organic Compounds." J. Steiglitz J. Am. Chem. Soc. 1922, 44, 1293. Hase, T. A. "Umpoled Synthons. A Survey of Sources and Uses in Synthesis".; John Wiley & Sons, Inc.: New York, 1987. Ho, T.-L. "Polarity Control for Synthesis"; John Wiley & Sons, Inc.: New York, 1991. Ono, N., "The Nitro Group in Organic Synthesis", Wiley-VCH, 2001 1) HO – 2) H3O Nef Reaction + Provide a mechanism for the Nef reaction Monographs: Papers of Historical Interest: Cume Question: The von Richter reaction is illustrated in the accompanying equation. Please provide a plausible mechanism for this transformation taking into account the following observations. (a) If 15 N-labeled KCN is used, the N 2 formed is half labeled; (b) 3-bromo-benzonitrile does not form 3-bromo-benzoic acid under the reaction conditions. heat, aqueous EtOH + Several Interesting Problems
D.A. Evans Ambiphilic Functional Groups Chem 206 Required Reading Arthur Lapworth(1872-1941) Applications to the Construction of Difunctional Relationships. "soups. Lapworth was among the first to understand and conceptualize the effect n Organizational Scheme for the Classification of Functional GI of heteroatomic substituents on the reactivity of individual carbon centers D.A. Evans Unpublished manuscript and how this effect is propagated through the carbon framework of organic molecules Methods of Reactivity Umpolung D. Seebach Angew. Chem. Int. Ed. Engl. 1979, 18, 239 Lapworth's Theory of Alternating Polarities Nitroaliphatic Compounds-ldeal Intermediates in Organic Synthesis Seebach. d, et al. chimia. 1979. 33. 1-18. "Latent Polarities of Atoms and Mechanism of Reaction, with Special Reference to Carbonyl Compounds A Lapworth Mem. Manchester. Lit. Phil. Soc. 1920, 64 (3) Papers of Historical Interest Arthur Lapworth: The Genesis of Reaction Mechanism " The addition of electrolytes to the carbonyl compound invariably M. Saltzman chem. ed 1972. 49. 750 proceeded as if the carbon were more positive than the oxygen atom, and invariably selected the negative ion; for example A Theoretical Derivation of the Principle of Induced Alternate Polarities A. Lapworth J. Chem. Soc. 1922, 121, 416 ④x=⊙ "The Electron Theory of Valence as Applied to Organic Compounds J. Steiglitz J. Am. Chem. Soc. 1922, 44, 1293 The extension of the infiuence of the directing, or"key atom, "over a long range seems to require for its fullest display the presence of double NuSeaphit ement of Aliphatic Nitro Groups by Carbon& Heteroatom bonds, and usually in conjugated positions iles. "R. Tamura, A Kamimura, N. Ono Synthesis 1991, 423 Functionalized Nitroalkanes as Useful Reagents for Alkyl Anion Synthons. G Rosini, R. Ballini Synthesis 1988, 833 Conjugated Nitroalkenes: Versatile Intermediates in Organic Synthesis A.G. M. Barrett. GG Graboski chem Rev 1986.. 751 The key atom" is the one with the most electronegative character, in this case the carbonyl oxygen Monographs Hase, T. A"Umpoled Synthons A Survey of Sources and Uses in anionoid/cationoid -nucleophilic/electrophilic Synthesis", John Wiley Sons, Inc: New York, 1987 The Lapworth polarity designations can be used to form the basis Ho, T.-L. "Polarity Control for Synthesis", John Wiley Sons, Inc: New of a functional group classification scheme York. 1991
D. A. Evans Ambiphilic Functional Groups Chem 206 Arthur Lapworth (1872–1941) Lapworth was among the first to understand and conceptualize the effect of heteroatomic substituents on the reactivity of individual carbon centers, and how this effect is propagated through the carbon framework of organic molecules. "Latent Polarities of Atoms and Mechanism of Reaction, with Special Reference to Carbonyl Compounds." A. Lapworth Mem. Manchester. Lit. Phil. Soc. 1920, 64 (3), 1. "The extension of the influence of the directing, or "key atom," over a long range seems to require for its fullest display the presence of double bonds, and usually in conjugated positions...." The "key atom" is the one with the most electronegative character, in this case the carbonyl oxygen. "The addition of electrolytes to the carbonyl compound invariably proceeded as if the carbon were more positive than the oxygen atom, and invariably selected the negative ion; for example:" Lapworth's Theory of Alternating Polarities: anionoid/cationoid nucleophilic/electrophilic The Lapworth polarity designations can be used to form the basis of a functional group classification scheme. Required Reading: "An Organizational Scheme for the Classification of Functional Groups. Applications to the Construction of Difunctional Relationships." D. A. Evans Unpublished manuscript. "Methods of Reactivity Umpolung." D. Seebach Angew. Chem. Int. Ed. Engl. 1979, 18, 239. "Nitroaliphatic Compounds–Ideal Intermediates in Organic Synthesis"' Seebach, D. et. al, Chimia, 1979, 33, 1-18. Papers of Historical Interest: "Arthur Lapworth: The Genesis of Reaction Mechanism." M. Saltzman J. Chem. Ed. 1972, 49, 750. "A Theoretical Derivation of the Principle of Induced Alternate Polarities." A. Lapworth J. Chem. Soc. 1922, 121, 416. "The Electron Theory of Valence as Applied to Organic Compounds." J. Steiglitz J. Am. Chem. Soc. 1922, 44, 1293. ––––––––––––––––––––– "Displacement of Aliphatic Nitro Groups by Carbon & Heteroatom Nucleophiles." R. Tamura, A. Kamimura, N. Ono Synthesis 1991, 423. "Functionalized Nitroalkanes as Useful Reagents for Alkyl Anion Synthons." G. Rosini, R. Ballini Synthesis 1988, 833. "Conjugated Nitroalkenes: Versatile Intermediates in Organic Synthesis." A. G. M. Barrett, G. G. Graboski Chem. Rev. 1986, 86, 751. Monographs: Hase, T. A. "Umpoled Synthons. A Survey of Sources and Uses in Synthesis".; John Wiley & Sons, Inc.: New York, 1987. Ho, T.-L. "Polarity Control for Synthesis"; John Wiley & Sons, Inc.: New York, 1991
D. A. Evans Reactivity Patterns of Functional Groups: Charge Affinity Patterns Chem 206 a Polar nxns form the basis set of bond constructions in synthesis The actual reaction associated with this transform is the addition of organometals to carbonyl substrates a Generalizations on conferred site reactivity will therefore be important Given this target RT bH2 CH3-CH--CH and the desire to form this bond The functional group =o dictates"the following bond construction When one considers the polar resonance structure for the c=o group it is clear that an CH3-CH O atom is very good at stabilizing an adjacent (+)charge through resonand a Consider polar disconnections of the illustrated B-hydroxy ketone 1 a Conferred site reactivity of =o 0() R Charge Affinity Patterns R—C—CH2=CHz=OH (+)()(+)(+) 0() I Use the descriptors(+)and(-)to denote the polar disconnections shown R—C—CH=二cHzH2O AB It is evident that the heteroatom functional groups, =0 and-OH, strongly bias (+)() the indicated polar disconnect a In the transforms illustrated above, symbols(+)&(-)are used to denote the particular polar transform illustrated Charge Affinity Patterns of Common Functional Groups In the present case there is NO INTRINSIC BIAS in favoring one transform over he other Me-CH2-CH2-Br ets now add an OH functional group(Fg)to propane at C-2 and see whether one creates a bias in the favoring of one or the other transforms Me-CH2-C=0 8- CH3-CH--CH3 favored
R R O CH O CH3 M CH3 O R M R O R R M O R R R R O A B A B CH3 CH CH3 OH CH3 CH: – OH CH3 CH CH3 OH CH3 CH + OH CH3 CH O – R C CH2 O CH2 OH CH C O OR H2C H2C CH CH2 OH CH2 C O H Me Me CH2 CH2 Br B+ B:– TB TA TA TB CH OM CH3 CH3 R C CH3 O C C C E1 C C C E2 C C C E4 C C C E3 R C CH O CH2 H2O CH2 O D. A. Evans Chem 206 ■ Polar rxns form the basis set of bond constructions in synthesis ■ Generalizations on conferred site reactivity will therefore be important Given this target and the desire to form this bond The functional group =O "dictates" the following bond construction ■ Conferred site reactivity of =O (+) (–) (+) ■ In the transforms illustrated above, symbols (+) & (–) are used to denote the particular polar transform illustrated. In the present case there is NO INTRINSIC BIAS in favoring one transform over the other. (+) (–) (–) (+) A: – A: + ■ Use the descriptors (+) and (–) to denote the polar disconnections shown. Charge Affinity Patterns Reactivity Patterns of Functional Groups: Charge Affinity Patterns Let's now add an OH functional group (FG) to propane at C-2 and see whether one creates a bias in the favoring of one or the other transforms: ■ The actual reaction associated with this transform is the addition of organometals to carbonyl substrates. (+) (–) – : CH3 + CH3 (–) (+) – CH3 + M + When one considers the polar resonance structure for the C=O group it is clear that an O atom is very good at stabilizing an adjacent (+) charge through resonance. favored disfavored ■ Consider polar disconnections of the illustrated b-hydroxy ketone 1: (+) (–) (+) (–) (–) (–) (+) (–) (+) (–) (–) (+) (–) (+) (–) 1 It is evident that the heteroatom functional groups, =O and -OH, strongly bias the indicated polar disconnections. (–) (+) (–) (+) (+) (+) (+) (+) Charge Affinity Patterns of Common Functional Groups
D. A. Evans Classification of Functional Groups Chem 206 Functional groups activate the carbon skeleton at the point of attachmentA-Functions: by either induction resonance. A 3rd hypothetical FG, designated as A, may be defined that has an Induction (+ unbiased charge affinity pattem as in 1. Such an idealized FG's activates all C-M1 C-F2 C-F3 CF4 sites to both nucleophilic and electrophilic reactions, and as such include Resonance (+ those functions classifies as either E-or G- The importance of introducing this third class designation is that it includes those functional groups having non-altermate charge affinity pattens such as 2-4 Sy C-E E= electrophilic at the point of attachment Hypothetical A-function A= ambiphilic at the pont of attachment (+-)(+-)(+ G= nucleophilic at the point of attachment For simplicity, we will designate three FG classes according to the designations provided above E& G-Functions. FG-Classification Rules To organize activating functions into common categories it is worthwhile to define hypothetical" functional groups E, and G, having the charge affinity In the proposed classification scheme the following rules followed in the atterns denoted below assignment of class designation of a given FG Hypothetical E-function Hypothetical G-function a Activating functions are to be considered as heteroatoms appended to or included within the carbon skeleton (+)(-)(+) (-)(+)(-) I Activating functions are inspected and classified according to their ation state of the carbon skeleton such functional groups confer icated polar site reactivity patterns toward both electrophiles a Since proton removal and addition processes are frequently an integral aspect of FG activation, the FG, its conjugate acid or base, and its proton Any FG that conforms either to the ideal charge affinity parrern or a tautomers are considered together in determining its class designation sub-pattern thereof will thus be classified as either an E-or G functi I The oxidation state of the FG is deemphasized since this is a subordinate Representative E-functions strategic consideration Me-CH2-CH2-Br Common E-Functions: Symbol: (+)C-E exception: -N H2C=CH-cH2-OHc—C -x, X= halogen Also consider all combinations of of above FGs;e.g=0+ OR
C E (+) C F1 (+) (+) C F2 C F3 C F4 C A C G C C C E C C C G CH C O OR H2C H2C CH CH2 OH CH2 C O H Me Me CH2 CH2 Br C C C E1 C C C E2 C C C E3 C C C E4 C C C E C C C A C C A C C A C A OR O O C E NR2 NR N X, X = halogen D. A. Evans Chem 206 ■ Activating functions are to be considered as heteroatoms appended to or included within the carbon skeleton. ■ Activating functions are inspected and classified according to their observed polar site reactivities. ■ Since proton removal and addition processes are frequently an integral aspect of FG activation, the FG, its conjugate acid or base, and its proton tautomers are considered together in determining its class designation. ■ The oxidation state of the FG is deemphasized since this is a subordinate strategic consideration. Induction Resonance (+) (–) (+) (–) (–) (–) Symbol (±) (–) Functional groups activate the carbon skeleton at the point of attachment by either induction & resonance. E = electrophilic at the point of attachment A = ambiphilic at the pont of attachment G = nucleophilic at the point of attachment For simplicity, we will designate three FG classes according to the designations provided above. E & G-Functions: To organize activating functions into common categories it is worthwhile to define "hypothetical" functional groups E, and G, having the charge affinity patterns denoted below. (+) (–) (+) (–) (+) (–) Hypothetical E-function Hypothetical G-function Classification of Functional Groups (–) (+) (–) (+) (+) (+) (+) (+) (+) (–) (+) Given the appropriate oxidation state of the carbon skeleton, such functional groups confer the indicated polar site reactivity patterns toward both electrophiles and nucleophiles. Any FG that conforms either to the ideal charge affinity parrern or a sub-pattern thereof will thus be classified as either an E- or G-function. Representative E-functions: Hypothetical A-function (+–) (+–) (+–) (+) (+) (–) (–) 1 (+–) 2 3 4 FG-Classification Rules A-Functions: A 3rd hypothetical FG, designated as A, may be defined that has an unbiased charge affinity pattern as in 1. Such an idealized FG's activates all sites to both nucleophilic and electrophilic reactions, and as such include those functions classifies as either E– or G–. The importance of introducing this third class designation is that it includes those functional groups having non-alternate charge affinity patterns such as 2–4. In the proposed classification scheme the following rules followed in the assignment of class designation of a given FG. Also consider all combinations of of above FGs; e.g =O + OR exception: exception: Common E-Functions: Symbol: (+)
D. A. Evans Classification of Functional Groups Chem 206 Common G-Functions: Symbol: (-)C-G conjugate acid Typical G-class functions are the Group l-IV metals whose reactivity patterns falls into a subset of the idealized g-FG 5 仓NCH2R oN=CHR AN=CHR ④N=CHR (-)(+)(-) H2C=CH-CH2-Li FGc(FG—C+) (- CH3-CH2-MgBr The reaction CH-R Common A-Functions: Symbol: (+)C-A E(+)9 A-functions are usually more structurally complex FGs composed of polyatomic assemblages of nitrogen, oxygen and their heavier Group V and VI relatives(P, As, S, Se) pKa- 10 0 +N-CH-R Typical A-functions, classified by inspection, are provided below -NO2=NOR=NNR2-N(OR -N2 =N mm总h SR—S(OR-S02R-SR2 -PR 2-P(O)R 2-PR a This reactivity pattern may be extended via conjugation IThese FGs are capable of conferring both(+)and (-)at point of attachment. The reaction N一CH=CHR N 一 CH2-CH-Nu X -0 X=OR, NR2 N=CH-CH-R Remarkably, the dual electronic properties of oximes were first discussed by 0()(+) Lapworth in 1924 before the modem concepts of valence bond resonance Charge affinity patterm: +N-CH=CH-R were developed Lapworth, A. Chemistry and Industry 1924, 43, 1294-1295 The Nitro Functional Group I The resonance feature which has been exploited As an example, the class designation of the nitro function is determined by an evaluation of the parent function, its nitronic acid tautomer, as well as conjugate acid and base
PR3 + N CH CH R –O –O + + H2C CH CH2 Li CH3 CH2 MgBr C A C G C C C G N O O CH2R + N O –O CH2R N HO O CHR NO2 NOR SR PR2 P(O)R2 NNR2 N(O)R N2 N S(O)R SO2R SR2 R H N X: R H N X: R H N X: R H N X: N X: R H + N O –O CH CH R + N CH–R –O –O + N CH–R –O O FG C N O O CHR R H N X: FG C + N CH2 CH Nu –O O R N HO HO CHR + N CH CH R –O O + N CH2–R –O O + N –O O R El D. A. Evans Classification of Functional Groups Chem 206 Typical G-class functions are the Group I-IV metals whose reactivity patterns, falls into a subset of the idealized G-FG 5. Common G-Functions: Symbol: (–) 5 (–) (+) (–) (–) (–) (–) Common A-Functions: Symbol: A-functions are usually more structurally complex FGs composed of polyatomic assemblages of nitrogen, oxygen and their heavier Group V and VI relatives (P, As, S, Se). Typical A-functions, classified by inspection, are provided below + (±) ■ These FG's are capable of conferring both (+) and (–) at point of attachment. (+) (+) (–) (–) X = OR, NR2 Remarkably, the dual electronic properties of oximes were first discussed by Lapworth in 1924 before the modern concepts of valence bond resonance were developed. Lapworth, A. Chemistry and Industry 1924, 43, 1294-1295. ■ This reactivity pattern may be extended via conjugation: (–) The charge affinity pattern: – ● ● The Reaction: El(+) pKa ~ 10 base The Nitro Functional Group ✔✔ (–) (+) Charge affinity pattern: The Reaction: (–) (+) Nu(–) ■ The resonance feature which has been exploited: (+) (+) (–) (–) X = OR, NR2 As an example, the class designation of the nitro function is determined by an evaluation of the parent function, its nitronic acid tautomer, as well as conjugate acid and base. H-tautomer conjugate base conjugate acid (–) (+)
D. A. Evans Charge Affinity Patterns and the Nitro Functional Group Chem 206 Some Reactions of the Nitro Functional Group The Nef reaction R Overall Transformation: 1)HO +N一CH=CHR EtOH R nitronate anion nitronic acid O2N R3N N-H H20 O2N. Et-NH The charge affinity patterns represented R Important Transformations of the -NO2 Functional Group HO H2 ■ Reduction n is quite facile o2N-c(-) Pd, Ni Pt etc R NH Synthesis 1986 ■ Nef reaction a The resonance features which have been exploited VV X=OR, NR2 Org. Reactions 1990, 38, 655 R(+H R(-)H O2N-C(-)
O H R R O R H R + + + N R R HO HO + N – O HO R R O R R H2O + N HO HO R R + N R R HO – O R H N X: O2N C(+) O2N C(–) H2O N HO HO R R OH + N R R – O – O + N R R O – O H O2N C(–) OH N R R HO HO + N – O – O R R R H N X: + N H – O O R R + N R R O – O H O2N C(+) N X: R H N H HO HO NO2 R O R OH R NO2 O2N Me O CO2Me Me N H O2N EtOH EtOH Et–NH2 EtOH EtOH O R O NH2 R O O R O H R O O2N O2N H2 R3SnH D R NO2 R NO2 MeO Me O O NO2 R O O R NO2 + N CH CH R –O O D. A. Evans Chem 206 (+) R3N (+) (–) (+) R3N R3N (–) (+) (–) (+) Some Reactions of the Nitro Functional Group ■ Nef Reaction: HO – H3O + rxn is quite facile Pd, Ni, Pt etc ■ Reduction: Important Transformations of the -NO2 Functional Group - H + H + nitronic acid ■ Mechanism ■ Overall Transformation: H HO + – nitronate anion 1) HO – 2) H3O + The Nef Reaction ✔✔ ✔✔ ■ The resonance features which have been exploited: (+) (+) (–) (–) X = OR, NR2 (+) (±) (+) (±) (–) The charge affinity patterns represented nitronate anion HO – H + nitronic acid H + - H + Charge Affinity Patterns and the Nitro Functional Group Pinnick, Org. Reactions 1990, 38, 655 Ono, N.; Kaji, A. Synthesis 1986, 693
D A. Evans Charge Affinity Patterns and the Nitro Functional Group Chem 206 Other Nonalernate Behavior of-NO2 FG Representative examples: O2N 6-2 O CH2R 2 LDA Ph PhCH2Br o CO2Et PhCH2Br o nitronate dianion + N nitronate dianion CO2Et 2LDA Seebach et al. Tetrahedron Lett. 1977. 1161-1164 80% yield O2N--G-C O2N--G-C NO2 As a Leaving Group Seebach et al. Tetrahedron Lett. 1977. 1161-1164 Review. Tamura et al. Synthesis 1991, 423-434 Nitroaliphatic Compounds-ldeal Intermediates in Organic Synthesis Seebach D. etal. Chimia. 1979. 33. 1-18 Representative examples:O2N-C-C Representative examples: O2 N-C(+) CH2Me -O Et PhCH2 Br Q CHzMe SnCl4 2 BuLi NO2 Me3 65%
N O O CH R R Nu CH R R + N – O O CH2R + N – O O Ph + N – O O CH2Me 2 BuLi 2 BuLi O2N C C + N – O CH2R – O + N CHR H – O – O H + N – O Et – O + N – O Ph – O O2N C C PhCH2Br Et–I O2N C C + N – O – O H CH2 N CH2 H – O – O + N – O O Ph Et + N – O O CH2Me Bn + N – O O CO2Et + N – O O Ph Me Me SPh NO2 NO2 Ph + N – O – O Ph + N – O – O CO2Et O2N C C SiMe3 SnCl4 O2N C(+) TiCl4 PhCH2Br PhCH2Br Ph Me Me SPh + N – O O Bn Ph + N – O O Bn CO2Et D. A. Evans Chem 206 nitronate dianion Reactivity Patterns (–) (–) – ● ● base base Other Nonalternate Behavior of –NO2 FG Charge Affinity Patterns and the Nitro Functional Group – ● ● base 2(–) Seebach et. al. Tetrahedron Lett. 1977, 1161-1164 Representative examples: – ● ● 51% yield – ● ● 80% yield 40% yield 2(–) Representative examples: (–) (–) 80% yield Seebach et. al. Tetrahedron Lett. 1977, 1161-1164 2 LDA 2 LDA –NO2 As a Leaving Group Representative examples: – + Nu(–) + NO2 – 74% 65% Review: Tamura et. al. Synthesis 1991, 423-434. "Nitroaliphatic Compounds–Ideal Intermediates in Organic Synthesis"' Seebach, D. etal, Chimia, 1979, 33, 1-18 nitronate dianion
D. A. Evans The Nitro Function as a Leaving Group Chem 206 NO2 As a Leaving Group CO2Et Representative examples: O2 N-C(+) (+) No R McMurry etal. Chem Comm. 1971 488-489. O2N R2N SPh Bakuzis etal. Tetrahedron Lett. 1978 2371. O2M 6y Pd(PPh3) DBU I NO2 Nao SPh Pd(PPh3)3 O2N-C-C CO2Et
N O O CH R R Nu CH R R Me Me SPh NO2 NO2 Ph SiMe3 SnCl4 NO2 N H Pd(PPh3 )3 NaCH(CO2Me)2 NaO2SPh Pd(PPh3 )3 Pd(PPh3 )3 TiCl4 O2N C SO2Ph Ph Me Me SPh CH(CO2Me)2 N(CH2)5 O N O O2N C C MeO CO2Et NO2 R3N CO2Et NO2 O2N C C O CO2Et CO2Et NO2 CO2Et NO2 O R2NH –NO2 – N O CO2Et NO2 R2NH H3O + DBU O2N C C O2N C C O CO2Et NO2 NO2 MeO CO2Et MeO CO2Et –NO2 – CO2Et O O2N C C D. A. Evans The Nitro Function as a Leaving Group Chem 206 –NO2 As a Leaving Group Representative examples: (+) – + Nu(–) + NO2 – 74% 65% + (+) (+) McMurry etal. Chem Comm. 1971 488-489. (+) (+) + (+) (+) Danishefsky etal. JACS 1978, 100, 2918. (+) (+) (–) (+) Bakuzis etal. Tetrahedron Lett. 1978 2371. (+) (–) (+) (+)
D. A. Evans Other Functional Groups with Non-alternate Reactivity Patterns Chem 206 The Diazo Functional Group Acid Catalyzed Reactions of Diazo Compounds H Review: Smith Tet. 1981 2407 a Both(+)and(-)reactivity patterns suggested by resonance structures H ■ Rxns with acids R时一NxH HCXN三N Diazocarbonyl Diazonium Common acids include BF3OEt2, HBF4. TFA, etc. N2=C-R N2=c-R Mechanism of activation is unclear for both Lewis and protic acids activation ay occur by protonation on C or o I Initiating reactivity is (-) subsequent reactivity is (+ a Ring expansion reactions: o Acid-Catalyzed Reactions EtoH N2-C-R N2-C-R N2-=C-R +) 96%) Mander. Chem. Comm. 1971773 N2-C-R Tet,1991134 Restriction: Starting ketone must be more reactive than product ketone become familiar with the peculiarities of a Precursors to Carbenes: N2C methane), it occurred to us that we might C=NEN N三N O filled( 25°C,2min Gibberellic Acid E EG H (82%) cs1980662
H X C N N R H C N H R N C N N R H N2 C R N2 C R D N2 C O C N N R H H C N H R N – N N C H R E G C: H R C: H R EtOH CH2N2 HO CH2–N2 N2 C R C R H C N N R H O H C X H R N2 C R N N OMe O N2 Cl3COCO HO O N2 H3C CH3 O N N TFA H + O O OCOCCl3 O O H3C CH3 O N N N2 C R N2 C R N2 C R D. A. Evans Other Functional Groups with Non-alternate Reactivity Patterns Chem 206 ■ Initiating reactivity is (–); subsequent reactivity is (+) (+) (–) X + – – + ■ Rxns with acids: ■ Both (+) and (–) reactivity patterns suggested by resonance structures + – + – + – The Diazo Functional Group empty (+) filled (–) + – ■ Precursors to Carbenes: Restriction: Starting ketone must be more reactive than product ketone (+) (–) + ■ Ring expansion reactions: (–) (+) (+, –) –E,G Acid Catalyzed Reactions of Diazo Compounds Review: Smith, Tet. 1981 2407 Diazocarbonyl Diazonium Common acids include BF3 •OEt2 , HBF4 , TFA, etc. Mechanism of activation is unclear for both Lewis and protic acids; activation may occur by protonation on C or O Acid-Catalyzed Reactions -25°C, 2 min (82%) Gibberrellic Acid Mander, JACS 1980 6626 TFA, -20°C (96%) "Having become familiar with the peculiarities of diazoketone chemistry while preparing [other compounds] (and, I might add, inured to handling uncomfortably large quantites of diazomethane), it occurred to us that we might be able to substitute a diazo group for bromine." Lewis Mander Mander, Chem. Comm. 1971 773 Tet., 1991 134 (–) (–) (+)
D. A. Evans Other Functional Groups with Non-alternate Reactivity Patterns Chem 206 More Acid Cataly Sulfur Functional Groups Olefins as nucleophiles Simpkins, N. S. Sulfones in Organic Synthesis; Pergamon, 1993 (100%) CH4 Sulfide Mander Smith's cyclopentenone ann pKa (-41) CH3-S-CH3 31*HOH Lindlar's cat(100%) Sulfonium salt Smith,7L19754225 (same acidity as phenol) (- )Reactivity Pattern Rearrangement 2s-C Nonalternate BF3OEt a Reactions with carbonyl compnds Mander. aust. J. chem. 1979 1975 ①W Polyene cyclizations ⊙R2S R2s- Smith, JACS 1981 2009 (一(
R O OBF3 N2 S CH3 CH3 CH3 S CH3 Me Me S Me Me C H H CH2 O S Me Me C H H S Me Me S Me Me CH2 O C H H S Me Me S Me Me Me O N2 Me HCl Me Me O N2 BF3 •OEt2 O R N2 O BF3 •OEt2 N2 O O Me Me BF3•OEt2 O Me Me O Me Me O Me Me Cl –N2 O Me Me O O R S O CH3 CH3 O CH3 S CH3 O O CH3 S CH3 O NaH O CH2 R2S C CH2 O R2S C R2S C CH4 HOH NH3 D. A. Evans Other Functional Groups with Non-alternate Reactivity Patterns Chem 206 Sulfur Functional Groups (+) (–) ■ Reactions with carbonyl compnds Nonalternate Reactivity Pattern (–) (+) Simpkins, N. S. Sulfones in Organic Synthesis.; Pergamon, 1993. pKa (~56) pKa 31 pKa (~41) Sulfide Sulfoxide Sulfone Sulfonium Salt pKa (DMSO) ~ 18 ~ 31 (45) ~35 Smith, TL 1975 4225 (40 - 65%) Lindlar's cat. (100%) Smith's cyclopentenone annulation: More Acid Catalysis Olefins as nucleophiles: (100%) Mander Jasmone Mander, Aust. J. Chem. 1979 1975 Rearrangement: Polyene cyclizations: 46% 12% + Smith, JACS 1981 2009 (same acidity as phenol)
