http://www.courses.fas.harvard.edu/~chem206/ Br NO2 KCN N R R O O H Br CO2H N2 O R R Chem 206D. A. Evans 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 a73 Historical Perspective a73 Charge Affinity Patterns a73 Functional Group Classification Scheme a73 The Chemistry of the –NO2 Group a73 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 D. A. Evans Unpublished manuscript (Lecture 26A, pdf) "Methods of Reactivity Umpolung."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 α-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 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 SpecialReference 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. R R O CHOCH 3 M CH3 O R M R O RR M O RR R R O A B A B CH3 CH CH3 OH CH3 CH: – OH CH CH3CH3 OH CH3 CH + OH CH3 CH O – R C CH2 O CH2 OH CH C O OR H2C CH CH2 OHH2C CH2 C O H Me CH2 CH2 BrMe B+ B:– TB TA TA TB CH OM CH3CH3 R C CH3 O C C E1C C C E2C C C E4C C C E3C R C CH O CH2 H2O CH2 O D. A. Evans Chem 206 a73 Polar rxns form the basis set of bond constructions in synthesis a73 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 a73 Conferred site reactivity of =O (+) (–)(+) a73 In the transforms illustrated above, symbols (+) & (–) are used to denote theparticular polar transform illustrated. In the present case there is NO INTRINSIC BIAS in favoring one transform over the other. (+) (– ) (–) (+) A: – A: + a73 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: a73 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 a73 Consider polar disconnections of the illustrated β-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 C E (+) C F1(+) (+) C F2 C F3 C F4 C GC A C C EC C C GC CH C O OR H2C CH CH2 OHH2C CH2 C O H Me CH2 CH2 BrMe C C E1C C C E2C C C E3C C C E4C C C EC C C AC C C A C C A C A OR O O C E NR2 NR N X, X = halogen Chem 206D. A. Evans a73 Activating functions are to be considered as heteroatoms appended to or included within the carbon skeleton. a73 Activating functions are inspected and classified according to their observed polar site reactivities. a73 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. a73 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 attachmentA = 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: PR3 CH RCH+ N –O –O + + CH CH2 LiH2C CH3 CH2 MgBr C A C G C C GC 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: HR + 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 CH NuCH2+ N –O O R N HO HO CHR CH RCH+ N –O O + N CH2–R –O O + N –O O R El D. A. Evans Chem 206Classification of Functional Groups 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 + (±) a73 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. a73 This reactivity pattern may be extended via conjugation: (–) The charge affinity pattern: – a71 a71 The Reaction: El(+) pKa ~ 10 base The Nitro Functional Group a20a20 (+)(–)Charge affinity pattern: The Reaction: (+)(–)Nu(–) a73 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 (–) (+) O H R R O R RH + + + 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: H+ N – O O R R + N R R O – O H O2N C(+) N X: HR N H HO HO NO2 R O R OH R NO2 O2N Me O CO2Me Me NH O2N EtOH EtOH Et–NH2 EtOH EtOH O R O NH2 R O O R O RH O O2N O2N H2 R3SnH ? R NO2 NO2R MeO Me OO NO2 R O O R NO2 CH RCH+ N –O O D. A. Evans Chem 206 (+) R3N (+) (–) (+) R3N R3N (+)(–)(+)(–) Some Reactions of the Nitro Functional Group a73 Nef Reaction: HO – H3O + rxn is quite facilePd, Ni, Pt etca73 Reduction: Important Transformations of the -NO2 Functional Group - H + H + nitronic acid a73 Mechanism a73 Overall Transformation: H +HO – nitronate anion 1) HO – 2) H3O + The Nef Reaction a20a20 a20a20 a73 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. 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 CH2R– O – O + N CHR H – O – O H + N Et– O – O + N Ph– O – 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 (–)(–) –a71 a71 basebase Other Nonalternate Behavior of –NO2 FG Charge Affinity Patterns and the Nitro Functional Group – a71 a71 base 2(–) Seebach et. al. Tetrahedron Lett. 1977, 1161-1164 Representative examples: –a71 a71 51% yield –a71 a71 80% yield 40% yield 2(–) Representative examples: (–)(–) 80% yieldSeebach 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 N O O CH R R Nu CH R R Me Me SPh NO2 NO2 Ph SiMe3 SnCl4 NO2 NH 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 CO2EtMeO CO2EtMeO –NO2– CO2Et O O2N C C D. A. Evans Chem 206The Nitro Function as a Leaving Group –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. (+) (–) (+) (+) H X N NC R H C N H R N N NC R H RCN2 N2 C R ? N2 C O N NC 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 RCN2 CRH N NC R H O CH X H R N2 C R N N OMe O N2Cl3COCO HO O N2 H3C CH3 O N N TFA H+ O O OCOCCl3 O O H3C CH3 O N N RCN2 N2 C R RCN2 D. A. Evans Chem 206Other Functional Groups with Non-alternate Reactivity Patterns a73 Initiating reactivity is (–); subsequent reactivity is (+) (+)(–) X –+– + a73 Rxns with acids: a73 Both (+) and (–) reactivity patterns suggested by resonance structures + – +––+ The Diazo Functional Group empty (+) filled (–) + – a73 Precursors to Carbenes: Restriction: Starting ketone must be more reactive than product ketone (+)(–) + a73 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 forbromine." Lewis Mander Mander, Chem. Comm. 1971 773 Tet., 1991 134 (–) (–) (+) 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 MeO N2Me HCl Me Me O N2 BF3?OEt2 O R N2 O BF3?OEt2 N2 O OMe Me BF3?OEt2 O Me Me O Me Me O Me Me Cl –N2 OMe Me O O R S O CH3CH3 O SCH3 CH3 O O S CH3CH3 O NaH O CH2 R2S C CH2 O R2S C R2S C CH4 HOH NH3 D. A. Evans Chem 206Other Functional Groups with Non-alternate Reactivity Patterns Sulfur Functional Groups (+) (–) a73 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)