哈佛大学：《高等有机化学》（英文版）Lecture 26 A Advanced Organic Chemistry

Chemistry 206 Advanced Organic Chemistry Handout-26A An Organizational Format for the Classification of Functional Groups. Applications to the Construction of Difunctional Relationships D. A. Evans Matthew d. shair Monday November 18.2002

Chemistry 206 Advanced Organic Chemistry Handout–26A Matthew D. Shair Monday , November 18, 2002 An Organizational Format for the Classification of Functional Groups. Applications to the Construction of Difunctional Relationships D. A. Evans

Chemistry 206, 2001 An Organizational format for the classification of Functional groups applica tions to the Construction of Difunctional Relationships D.A. Evans Department of chemistry Chemical Biology, Harvard University, Cambridge, MA, 02318 Introduction Among the subdisciplines of chemistry the area of organic synthesis is probably the least organized in terms of unifying concepts and general methodology This conclusion has been made quite obvious by the relative scarcity of critical monographs covering this important topic. I The wide structural diversity of organic molecules, the vast abundance of organic reactions, and the restrictions imposed upon these reactions when applied to the synthesis of a complex structure all contribute to the magnitude of the problem of making generalizations in this area However difficult the overall task of explicitly defining a priori a total synthesis of an organic tructure may be, there are certain simplifying features which can be developed to generate logical sets of potential synthetic pathways to a given molecular target. Some of the general guidelines which help to de fine this task have been outlined. 2 Recently, some of the problems associated with reducing synthetic de sign to a mathematical basis and the application of machine computation to synthetic analysis have been re- Difunctional Relationships. One aspect of the synthesis of any polyfunctional target structure deals with strategies associated with the construction of arrays of relationships between heteroatom func tional groups which may be denoted as FI, F2, etc. The general reactions illustrated below simply represent the union of two monofunctional organic fragments where the functional groups F1, F2 provide the necessary activation for the coupling process. In these reactions, the oxidation states of the associated car- bon fragments are purposely left undefined In relating the generalized notation below to a real situation, if F1-C-C were an enolate, Equation 1 might be used to represent a generalized aldol or Mannich reaction while equation 3 might represent a Michael reaction Henrickson has provided some useful generalizations on the construction of difunctional relation- ships which are worth summarizing. For example, he defines the construction span as the number of carbons linking FI and F2. In the cases illustrated above, the product of the reaction illustrated in Equation I has a construction span of three. The construction fragments are then defined as the monofunctional reactants, such as FI-C-C and F1-C. In general, construction spans are limited to six or less. This is a consequence of the fact that the operational utility of a given functional group diminishes as it is removed (a)Corey, E J, Cheng, X.M. The Le Synthesis; Wiley, New York, 1979.(b)Fuhrhop, J, Penzlin G. Organic Synthesis: Concepts, Methods Materials, Verlag Chemie, Weinheim, 1983.(c)Carruthers Some Modern Methods ofOrganic Synthesi ambridge Univ Press, Cambridge, 1987.(d)Organic Synthesis The Disconnection Approach, Wiley, Ne 82.(e) Payne, C. A, Payne, L B. How To Do An organic thesis; Allyn and Bacon., Boston, 1969 R E. Organic Synthesis, Prentice-Hall, Inc, Englewood Cliffs 3)(a)Hendrickson, J.B. J. Am. Chem. Soc. 1971, 93, 6487.()Ugi, I; Gillespie, P Angew.Chem Ed.1971,10, 914.(c)Corey, E.J., Wipke, W.T.; Cramer, Ill,R D; Howe, W.J.J. Am Chem. Soc. 1972, 94, 421(d) Corey E.J.; Cramer, Ill, R D; Howe, w.J. ibid. 1972, 94, 440, and earlier references cited therein.(e) Corey, E.J.; Howe, W.J., Pensak, D. A. ibid. 1974, 96, 7724(f) Blair, J; Gasteiger, J; Gillespie, C, Gillespie, P. D. Ugi, I etrahedron 1974, 30, 1845.(g) Bersohn, M.J. Chem. Soc., Perkin /1973, 1239 (a)Thakkar, A.J. Fortschritte Chem. Forschung 1973, 39,3.(b)Dungundji, J. Ugi, I. ibid. 1973, 39, 19(c) Gelernter, H, Sridharan, N.S., Hart, A J; Yen, S C, Fowler, F. W, Shue, J.J. ibid. 1973, 41, 113

Functional Group Classification Chemistry 206, 2001 An Organizational Format for the Classification of Functional Groups. Applica￾tions to the Construction of Difunctional Relationships D. A. Evans Department of Chemistry & Chemical Biology, Harvard University, Cambridge, MA, 02318 Introduction Among the subdisciplines of chemistry the area of organic synthesis is probably the least organized in terms of unifying concepts and general methodology. This conclusion has been made quite obvious by the relative scarcity of critical monographs covering this important topic.1 The wide structural diversity of organic molecules, the vast abundance of organic reactions, and the restrictions imposed upon these reactions when applied to the synthesis of a complex structure all contribute to the magnitude of the problem of making generalizations in this area. However difficult the overall task of explicitly defining a priori a total synthesis of an organic structure may be, there are certain simplifying features which can be developed to generate logical sets of potential synthetic pathways to a given molecular target . Some of the general guidelines which help to de￾fine this task have been outlined.2 Recently, some of the problems associated with reducing synthetic de￾sign to a mathematical basis and the application of machine computation to synthetic analysis have been re￾ported.3,4 Difunctional Relationships. One aspect of the synthesis of any polyfunctional target structure deals with strategies associated with the construction of arrays of relationships between heteroatom func￾tional groups which may be denoted as F1, F2, etc. The general reactions illustrated below simply represent the union of two monofunctional organic fragments where the functional groups F1, F2 provide the necessary activation for the coupling process. In these reactions, the oxidation states of the associated car￾bon fragments are purposely left undefined. In relating the generalized notation below to a real situation, if F1-C-C were an enolate, Equation 1 might be used to represent a generalized aldol or Mannich reaction while equation 3 might represent a Michael reaction. C C F1 F2 C C F2 C C F1 C C F1 C C C F2 C F2 C C F1 C C C C C C C C C C F1 F2 F1 F2 (3) (2) (1) + + + Henrickson has provided some useful generalizations on the construction of difunctional relation￾ships which are worth summarizing. For example, he defines the construction span as the number of carbons linking F1 and F2. In the cases illustrated above, the product of the reaction illustrated in Equation 1 has a construction span of three. The construction fragments are then defined as the monofunctional reactants, such as F1-C-C and F1-C. In general, construction spans are limited to six or less. This is a consequence of the fact that the operational utility of a given functional group diminishes as it is removed 1) (a) Corey, E. J.; Cheng, X.-M. The Logic of Chemical Synthesis; Wiley, New York, 1979. (b) Fuhrhop, J.; Penzlin, G. Organic Synthesis: Concepts, Methods, Startimg Materials; Verlag Chemie, Weinheim, 1983. (c) Carruthers, W. Some Modern Methods of Organic Synthesis, 3nd ed.; Cambridge Univ. Press, Cambridge, 1987. (d) Organic Synthesis, The Disconnection Approach; Wiley, New York, 1982. (e) Payne, C. A.; Payne, L.B. How To Do An Organic Synthesis; Allyn and Bacon., Boston, 1969. (f) Ireland, R. E. Organic Synthesis, Prentice-Hall, Inc., Englewood Cliffs, 1969. 2) (a) Corey, E. J. Pure Appl. Chem. 1967, 14, 19. (b) Corey, E. J. Quart. Rev. 1971, 25, 455. 3) (a) Hendrickson, J. B. J. Am. Chem. Soc. 1971, 93, 6487. (b) Ugi, I; Gillespie, P. Angew. Chem. Int. Ed. 1971, 10, 914. (c) Corey, E. J.; Wipke, W. T.; Cramer, III, R. D.; Howe, W. J. J. Am. Chem. Soc. 1972, 94, 421. (d) Corey, E. J.; Cramer, III, R. D.; Howe, W. J. ibid. 1972, 94, 440, and earlier references cited therein. (e) Corey, E. J.; Howe, W. J.; Pensak, D. A. ibid. 1974, 96, 7724. (f) Blair, J.; Gasteiger, J.; Gillespie, C.; Gillespie, P. D.; Ugi, I. Tetrahedron 1974, 30, 1845. (g) Bersohn, M. J. Chem. Soc., Perkin I 1973, 1239. 4) (a) Thakkar, A. J. Fortschritte Chem. Forschung 1973, 39, 3. (b) Dungundji, J.; Ugi, I. ibid. 1973, 39, 19. (c) Gelernter, H.; Sridharan, N. S.; Hart, A. J.; Yen, S. C.; Fowler, F. W.; Shue, J.-J. ibid. 1973, 41, 113

from the C-C bond being formed. The problem of site or ambident reactivity in systems possessing ex tended conjugation is the principal liability in the extension of the construction span. This point is illus trated below for both conjugate addition and enolate alkylation ( Scheme D) Scheme i the problem of ambident reactivity 1.6 Addition Meo a-alkylation 6 MeO2C Nu(-) 1. 4 Addition -==== MeO2C 人入 日(+) r-alkylation The objectives of the present discourse are to present an organizational format which can serve to correlate strategies for the construction simple pairwise functional group relationships. As a result of the overwhelming predisposition of nature to employ polar rather than free radical processes in the biosynthesis of organic compounds the chosen organizational format reflects this bias in reaction type The designation of reactions as polar is recognized to be rather arbitrary since known reactions vary widely in their polar character, ranging from essentially nonpolar radical reactions and weakly polar electrocyclic reactions to strongly polar ionic processes. Of primary concern in this discussion will be those reactions that involve charged species at some point along the reaction coordinate Charge Affinity Patterns. In order to describe an organizational model for the classification and synthesis of heteroatom- heteroatom A-B A B+(4) (difunctional)relationships in organic molecules, two familiar ideas will be employed. The first is that in a given target molecule the A-B B-(5) various bonds can be ionically "disconnected"(eq 4, 5). That is, if the A-B bond could be cleaved heterolytically, the indicated set of polar fragments would result This antithetic process suggests ionic precursors suitable for the construction of the target molecule via polar coupling processes. The second well accepted idea is that functional groups determine site reactivities on a carbon skeleton based upon known reactions. That is, the oxygen atom in both acetone and anisole dictates the site reactivities that are displayed for each molecule with nucleophilic and electrophilic reagents. Thus, if the molecule A-B contained one or he bond one pair of ionic precursors, eg 6 or 7, would be strongly favored A-B as plausible precursors. In such a case the favored ionic(+)( precursors to A-B could be symbolized with either(+)or()in the A-B o target molecule, e.g As an example, two possible polar disconnections for ketone 1 are illustrated below. The parity labels in the target structure suggest plausible monofunctional precursors from which the target structure can be assembled by polar processes. It is also evident that the heteroatom functional groups, =O and-OH, strongly bias the indicated polar disconnections Scheme II Polar Disconnections and Charge Affinity Pattterns T CH2=O CH2-CH2-OH T CHECH H2 5) The use of the symbols, (+)and (-), in no way represents formal positive or negative charges and will always be bracketed to denote this distinction. Other forms of notation have been considered such as(0)and (1)to denote a potential site of electrophilicity or nucleophilicity; however, the chosen symbols convey more direct information to the organic chemist

Functional Group Classification page 2 from the C-C bond being formed. The problem of site or ambident reactivity in systems possessing ex￾tended conjugation is the principal liability in the extension of the construction span. This point is illus￾trated below for both conjugate addition and enolate alkylation (Scheme I). MeO2C MeO2C R R Nu MeO2C R Nu MeO R OM MeO R MeO R O O El El Scheme I The Problem of Ambident Reactivity 4 6 g-alkylation a g Nu(-) El(+) El(+) H + H + a-alkylation 1,4 Addition 1,6 Addition H + H + Nu(-) The objectives of the present discourse are to present an organizational format which can serve to correlate strategies for the construction simple pairwise functional group relationships. As a result of the overwhelming predisposition of nature to employ polar rather than free radical processes in the biosynthesis of organic compounds the chosen organizational format reflects this bias in reaction type. The designation of reactions as polar is recognized to be rather arbitrary since known reactions vary widely in their polar character, ranging from essentially nonpolar radical reactions and weakly polar electrocyclic reactions to strongly polar ionic processes. Of primary concern in this discussion will be those reactions that involve charged species at some point along the reaction coordinate. Charge Affinity Patterns. In order to describe an organizational model for the classification and synthesis of heteroatom-heteroatom (difunctional) relationships in organic molecules, two familiar ideas will be employed. The first is that in a given target molecule the various bonds can be ionically "disconnected" (eq 4, 5). That is, if the A-B bond could be cleaved heterolytically, the indicated set of polar fragments would result. This antithetic process suggests ionic precursors suitable for the construction of the target molecule via polar coupling processes. The second well accepted idea is that functional groups determine site reactivities on a carbon skeleton based upon known reactions. That is, the oxygen atom in both acetone and anisole dictates the site reactivities that are displayed for each molecule with nucleophilic and electrophilic reagents. Thus, if the molecule A-B contained one or more functional groups proximal to the bond to be disconnected, one pair of ionic precursors, eq 6 or 7, would be strongly favored as plausible precursors. In such a case the favored ionic precursors to A-B could be symbolized with either (+) or (-) in the target molecule, e.g.5 As an example, two possible polar disconnections for ketone 1 are illustrated below. The parity labels in the target structure suggest plausible monofunctional precursors from which the target structure can be assembled by polar processes. It is also evident that the heteroatom functional groups, =O and -OH, strongly bias the indicated polar disconnections. R C CH3 O CH2 O R C CH2 O CH2 OH R C CH O CH2 TA TB (+) (–) (+) (–) (–) (–) (+) (–) (+) (–) (–) (+) (–) (+) (–) OH2 1 Scheme II Polar Disconnections and Charge Affinity Pattterns 5) The use of the symbols, (+) and (-), in no way represents formal positive or negative charges and will always be bracketed to denote this distinction. Other forms of notation have been considered such as (0) and (1) to denote a potential site of electrophilicity or nucleophilicity; however, the chosen symbols convey more direct information to the organic chemist. A B A B (5) A: – B+ (4) A: + B:– A B A B A: + B:– A: – B+ (–) (+) (+) (–) (6) (7)

For any given atom or heteroatom assemblage which is defined as a functional group linked to a carbon skeleton, the parity labels, (+ and(), may be employed to denote the positional polar site reactivity, or charge affinity pattern which the functional group confers upon the carbon framework. For the simple molecules shown below(Scheme III) containing a homogeneous set of activating functions, E, there are associated charge affinity patterns 2-5 of which each is a sub-pattern of the generalized structure 6. Note that the carbonyl function is defined as=o rather that C=O in this discussion. You might contemplate why this functional group is defined in this fashion Scheme Ill Charge Affinity Patterns of Common Functional Groups H3C-CH2-CH2-Br H2C〓CHCh 5 The notion that an organic structure can be viewed as an"ion assemblage"has an interesting history originating with the work of Lapworth and others. 6, 7 Although the ion assemblage viewpoint was developed historically to predict site reactivity in both aliphatic and aromatic systems, this description of an organic structure is equally instructive in defining rational sets of synthetic pathways for a given target structure employing heterolytic processes as the primary set of coupling reactions. Indeed, the thought processes associated with the construction of organic molecules operate intuitively to recognize many sub units of a given structure in terms of polar fragments. The present use of parity labels to denote viable polar fragments simply formalizes this intuition Classification of Functional Groups(FG) In order to organize general strategies that have been developed to construct heteroatom-heteroatom relationships from monofunctional precursors it is useful to develop a self-consistent classification scheme for single functional groups(FG) based on the concepts of polar disconnection and conferred site reactivity towards nucleophiles and electrophiles. The proposed scheme recognizes the dominate inductive and resonance components of various substituents and establishes& broad categories for activating functions which correlate similar conferred chemical properties to carbon g Four possible functional group cate ories(F1-F4)are shown below. Those FGs which are more electronegative than carbon provide in ductive activation defining the electrophilic potential at the point of attachment denoted as (+). In a com- plementary fashion, FGs which are less electronegative than carbon provide inductive activation creating nucleophilic potential at the point of attachment denoted as(). Since FG activation through induction and resonance are independent variables which contribute to the overall FG reactivity pattern, four possible classes of functional groups can be defined(Scheme IV). This discussion is reminiscent of the classifica- tion of FGs according to their impact on electrophilic aromatic substitution. 10 Scheme iv Classification of Functional groups (+) C Resonance (+ (±) (-) C-A 6)(a)Lapworth, A Mem. Proc. Manchester Lit. Phil. Soc. 1920, 64, 1.(b)Lapworth, A.J. C oc.1922,121, 416.(c)Lapworth, A Chem Ind. 1924, 43, 1294.(d) Lapworth, A. ibid. 1925, 44, 397. For an excellent review of Arthur Lapworth's contributions to chemistry see: Saltzman, M.J. Chem. Ed. 1972, 49, 750-753 (a) Vorlander, D. Chem. Ber:. 1919, 52B, 263 (b)Stieglitz, J.J. Am. Chem. Soc. 1922, 44, 1293 See reference 3c for an alternate classification scheme for functional groups For an analysis of the relative importance of field and resonance components of substitutent effects see: Swain, C. G E. C. Am C/ 1968,90,4328 0) March, J. Advanced Organic Chemistry, 4th ed, Wiley-Interscience New York, 1992; pp 507-512

Functional Group Classification page 3 For any given atom or heteroatom assemblage which is defined as a functional group linked to a carbon skeleton, the parity labels, (+) and (-), may be employed to denote the positional polar site reactivity, or charge affinity pattern which the functional group confers upon the carbon framework. For the simple molecules shown below (Scheme III) containing a homogeneous set of activating functions, E, there are associated charge affinity patterns 2 - 5 of which each is a sub-pattern of the generalized structure 6. Note that the carbonyl function is defined as =O rather that C=O in this discussion. You might contemplate why this functional group is defined in this fashion. CH C O OR H2C CH CH2 OH CH2 H2C C O H H3C H3C CH2 CH2 Br C C C E1 C C C E2 C C C E3 C C C E4 C C C E 2 (–) (+) (–) (+) (+) (+) (+) (+) 3 4 5 (+) (–) (+) 6 Scheme III Charge Affinity Patterns of Common Functional Groups The notion that an organic structure can be viewed as an "ion assemblage" has an interesting history originating with the work of Lapworth and others.6, 7 Although the ion assemblage viewpoint was developed historically to predict site reactivity in both aliphatic and aromatic systems, this description of an organic structure is equally instructive in defining rational sets of synthetic pathways for a given target structure employing heterolytic processes as the primary set of coupling reactions. Indeed, the thought processes associated with the construction of organic molecules operate intuitively to recognize many sub￾units of a given structure in terms of polar fragments. The present use of parity labels to denote viable polar fragments simply formalizes this intuition. Classification of Functional Groups (FG). In order to organize general strategies that have been developed to construct heteroatom-heteroatom relationships from monofunctional precursors it is useful to develop a self-consistent classification scheme for single functional groups (FG) based on the concepts of polar disconnection and conferred site reactivity towards nucleophiles and electrophiles. The proposed scheme recognizes the dominate inductive and resonance components of various substituents and establishes8 broad categories for activating functions which correlate similar conferred chemical properties to carbon.9 Four possible functional group cate￾gories (F1-F4) are shown below. Those FGs which are more electronegative than carbon provide in￾ductive activation defining the electrophilic potential at the point of attachment denoted as (+). In a com￾plementary fashion, FGs which are less electronegative than carbon provide inductive activation creating nucleophilic potential at the point of attachment denoted as (–). Since FG activation through induction and resonance are independent variables which contribute to the overall FG reactivity pattern, four possible classes of functional groups can be defined (Scheme IV). This discussion is reminiscent of the classifica￾tion of FGs according to their impact on electrophilic aromatic substitution.10 C F2 C F3 C F4 C E C A C G C F1 (+) Scheme IV Classification of Functional Groups Induction (+) Resonance (+) (–) (+) (–) (–) (–) Symbol (+) (±) (–) 6) (a) Lapworth, A. Mem. Proc. Manchester Lit. Phil. Soc. 1920, 64, 1. (b) Lapworth, A. J. Chem. Soc. 1922, 121, 416. (c) Lapworth, A. Chem. Ind. 1924, 43, 1294. (d) Lapworth, A. ibid. 1925, 44, 397. For an excellent review of Arthur Lapworth's contributions to chemistry see: Saltzman, M. J. Chem. Ed. 1972, 49, 750-753. 7) (a) Vorländer, D. Chem. Ber. 1919, 52B, 263. (b) Stieglitz, J. J. Am. Chem. Soc. 1922, 44, 1293. 8) See reference 3c for an alternate classification scheme for functional groups. 9) For an analysis of the relative importance of field and resonance components of substitutent effects see: Swain, C. G.; Lupton, Jr., E. C. J. Am. Chem. Soc. 1968, 90, 4328. 10) March, J. Advanced Organic Chemistry, 4th ed.; Wiley-Interscience: New York, 1992; pp 507-512

Functional Group Classification E& G-Functions. From the preceding discussion, one might (..)(/E-function the creation of four classes of functional groups, however, for the sake o simplicity, three FG class designations will be chosen. To organize activating (+)((+ functions into common categories it is worthwhile to define " hypothetical functional groups E, and G, I having the charge affinity patterns denoted in 6 nd 7 respectively. Given the appropriate oxidation state of the carbon skeleton such functional groups confer the indicated potential site reactivity patterns Hypothetical G-function towards both electrophilic and nucleophilic reagents. Any functional groups ((+)6 whose reactivity pattern conforms to the ideal pattern or to a sub-pattern of C-C-C-G these hypothetical functions will be thus classified as an E- or G-function respectively. For example, the halogen and oxygen-based functional groups in four molecules illustrated in Scheme Ill may be classified as E-functions since their respective charge affinity patterns conform to a subset of the charge affinity pattern of the hypothetical E-function A-Functions. A third hypothetical function, A, (A for amphoteric!) can be defined which has an unbiased charge Hypothetical A-function affinity pattern as in 8. Such an idealized functional group (+-( activates all sites to both nucleophilic and electrophilic reactions and. as such. include those functions classified as either e or g The importance of introducing this third class designation is that it includes those functional groups having non-al ternate charge affinity patterns as in 9, 10 and 11 The differentiation of polar reactivity patterns can be described in an alternative manner. Starting with an ideal A-function, one could imagine a process in which the reactivity pattern is gradually polarized towards E-or G-behavior(Scheme V). Since site reactivity is not an on-off property but varies continu- usly over a wide range, one could further subdivide a-class functions into those functions with a bias towards E-class or G-class properties. Such a bias could be denoted by the dominant subordinate charge affinity notation in 12 and 13; however, for the concepts to be presented in this discourse, such A-function subclasses are nonessential. It should be emphasized that the purpose of the E-and G-classification is not to rigidly pigeon-hole functional groups based on site reactivity, but only to separate those which are strongly polarized toward e or g behavior. The decision has been made to avoid the pursuit of an overly detailed FG classification scheme since such attempts will dangerously oversimplify problems since an es sentially contiguous function cannot be segmented in to discrete part Scheme V Alternate vs Nonalternate Reactivity Patterns Hypothetical A-function (+-)(+-)(+-) 8(_A Hypothetical E-function Hypothetical G-function I) The symbol E was selected to denote electrophilic at the point of attachment to the carbon skeleton Unfortunately,the symbol N cannot be used to represent those FGs which are nucleophilic at the point of attachment since this is also the symbol for nitrogen. To avoid this conflict, the symbol g was chosen for this FG class designation

Functional Group Classification page 4 E & G-Functions. From the preceding discussion, one might opt for the creation of four classes of functional groups; however, for the sake of simplicity, three FG class designations will be chosen. To organize activating functions into common categories it is worthwhile to define "hypothetical" functional groups E, and G,11 having the charge affinity patterns denoted in 6 and 7 respectively. Given the appropriate oxidation state of the carbon skeleton, such functional groups confer the indicated potential site reactivity patterns towards both electrophilic and nucleophilic reagents. Any functional groups whose reactivity pattern conforms to the ideal pattern or to a sub-pattern of these hypothetical functions will be thus classified as an E- or G-function respectively. For example, the halogen and oxygen-based functional groups in four molecules illustrated in Scheme III may be classified as E-functions since their respective charge affinity patterns conform to a subset of the charge affinity pattern of the hypothetical E-function. A-Functions. A third hypothetical function, A, (A for amphoteric!) can be defined which has an unbiased charge affinity pattern as in 8. Such an idealized functional group activates all sites to both nucleophilic and electrophilic reactions and, as such, include those functions classified 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 as in 9, 10 and 11. The differentiation of polar reactivity patterns can be described in an alternative manner. Starting with an ideal A-function, one could imagine a process in which the reactivity pattern is gradually polarized towards E- or G-behavior (Scheme V). Since site reactivity is not an on-off property but varies continu￾ously over a wide range, one could further subdivide A-class functions into those functions with a bias towards E-class or G-class properties. Such a bias could be denoted by the dominant subordinate charge affinity notation in 12 and 13; however, for the concepts to be presented in this discourse, such A-function subclasses are nonessential. It should be emphasized that the purpose of the E- and G-classification is not to rigidly pigeon-hole functional groups based on site reactivity, but only to separate those which are strongly polarized toward E or G behavior. The decision has been made to avoid the pursuit of an overly detailed FG classification scheme since such attempts will dangerously oversimplify problems since an es￾sentially contiguous function cannot be segmented in to discrete parts. C C C A C C C A C C C A C C C G C C C E (+–) (+–) (+–) 12 Hypothetical A-function (±) (±) (±) (±) (±) (±) (–) (+) (–) (+) (–) (+) Hypothetical E-function Hypothetical G-function Scheme V Alternate vs Nonalternate Reactivity Patterns 13 11) The symbol E was selected to denote electrophilic at the point of attachment to the carbon skeleton Unfortunately, the symbol N cannot be used to represent those FGs which are nucleophilic at the point of attachment since this is also the symbol for nitrogen. To avoid this conflict, the symbol G was chosen for this FG class designation. C C C E C C C G (+) (–) (+) 6 7 (–) (+) (–) Hypothetical E-function Hypothetical G-function C C C A C C A C C A C A Hypothetical A-function 8 (+–) (+–) (+–) 9 (+) (+) (–) (–) 10 11 (+–)

FG Classification Rules. In the proposed classification scheme the following rules are followed in the assignment of class designations to functional groups 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 reactivi- Since both proton removals and addition processes are frequently an integral component in functional group activation, the function, its conjugate acid or base, and its possible proton tautomers are considered together in determining its class designation The oxidation state of the FG is de-emphasized since this is a subordinate strategic considera E-Functions. For example, carbonyls and carbonyl derivatives will be represented as=X where X lay be either oxygen or substituted nitrogen. Well recognized exceptions to the polar class designations illustrated in Scheme I may be found in the chemistry of CO and HCN. In these instances the carbon bearing the heteroatom exhibits well-defined nucleophilic properties. Accordingly these two functional Table I. Common E-Functions: Symbolf+)C-E NR2 =NR exception X, X= halogen Also consider all combinations of of above FGs: e.g=0+ OR G-Functions. Typical G-class functions are the Group I-IV metals whose reactivity pattern, falls into a subset of 7 H2C-CH-CH2-Li CH3 CH2-MgBr tnnenA-Functions. A-functions are usually more structurally complex FGs composed of polyatomIc plages of nitrogen, oxygen and their heavier Group V and VI relatives(P, As, S, Se). Typical A functions, classified by inspection, are provided in Table II Table IL. Common A-Functions: Symbolt)C-A 一NO2=NR=NR=NOR=三N so2 R P(O)R2 --PR3 Functional groups possessing the following general structure, =N-X where X is a hetroatom oofectrops nonbonding electron pair, have an expanded set of resonance options which create either an ilic or nucleophilic potential at the point of attachment. Remarkably, the dual electronic pro oximes were first discussed by Lapworth2 in 1924 before the modern concepts of valence bond develo These FG's are capable of conferring both(+)and(-)at the point of attachme OR, NR 2)Lapworth, A Chemistry and Industry 1924, 43, 1294-1295

Functional Group Classification page 5 FG Classification Rules. In the proposed classification scheme the following rules are followed in the assignment of class designations to functional groups. ■ 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 reactivi￾ties. ■ Since both proton removals and addition processes are frequently an integral component in functional group activation, the function, its conjugate acid or base, and its possible proton tautomers are considered together in determining its class designation. ■ The oxidation state of the FG is de-emphasized since this is a subordinate strategic considera￾tion. E-Functions. For example, carbonyls and carbonyl derivatives will be represented as =X where X may be either oxygen or substituted nitrogen. Well recognized exceptions to the polar class designations illustrated in Scheme I may be found in the chemistry of CO and HCN. In these instances the carbon bearing the heteroatom exhibits well-defined nucleophilic properties. Accordingly these two functional groups will be classified as A-functions by inspection (vide infra). OR O O C E NR2 NR N X, X = halogen Also consider all combinations of of above FGs; e.g =O + OR exception: exception: Table I. Common E-Functions: Symbol: (+) G-Functions. Typical G-class functions are the Group I-IV metals whose reactivity pattern, falls into a subset of 7. H2C CH CH2 Li C C C G CH3 CH2 MgBr (–) (+) (–) (–) (–) (–) 7 A-Functions. 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 in Table II. NO2 NOR C A SR PR2 P(O)R2 NNR2 N(O)R N2 N S(O)R SO2R SR2 PR3 + + Table II. Common A-Functions: Symbol: (±) Functional groups possessing the following general structure, =N-X where X is a hetroatom bearing a nonbonding electron pair, have an expanded set of resonance options which create either an electrophilic or nucleophilic potential at the point of attachment. Remarkably, the dual electronic properties of oximes were first discussed by Lapworth12 in 1924 before the modern concepts of valence bond reso￾nance was developed. R H N X: R H N X: R H N X: ■ These FG's are capable of conferring both (+) and (–) at the point of attachment. (+) (+) (–) (–) X = OR, NR2 12) Lapworth, A. Chemistry and Industry 1924, 43, 1294-1295

A Case Study: The Nitro Group. 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 14 and 15 H-tautomet conjugate base conjugate base N一CH2R +N■cHR nitronic acid nitronate anion. 14 From the collection of transformations of the nitro group one finds that the dominate mode of reac tivity of the nitronate anion 14 is that of a G-function while the protonated nitronic acid 15 mirrors the re- activity of an E-functic The dominate polar site reactivit D FG-C The typical behavior of nitronate anions 14 is summarized in the representative transformations provided in Scheme VI. These moderately nucleophilic species, although they are not readily alkylated readily undergo aldol and conjugate addition reactions Scheme vi selected reactions of the nitronate anion oa The charge affinity pattern: NCH This reactivity pattern may be extended via conjugation It is no surprise that the charge affinity pattern of this fg may be extended by conjugation, an a,B-unsaturated nitro compounds readily participate in conjugate addition reactions(Scheme vil) Scheme vii selected reactions of the nitronate anion The Reaction 只、c=cH Nu(-) CH2-CH-Nu The charge affinity pattern Nitro aromatics. The resonance feature which has been exploited

Functional Group Classification page 6 A Case Study: The Nitro Group. 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 14 and 15. N O O CH2R N HO O CHR N O O CHR N HO HO CHR + – – + + – – H-tautomer conjugate base conjugate base + nitronic acid nitronate anion, 14 15 From the collection of transformations of the nitro group one finds that the dominate mode of reac￾tivity of the nitronate anion 14 is that of a G-function while the protonated nitronic acid 15 mirrors the re￾activity of an E-function. N HO HO CHR FG C N FG C O O CHR 15 14 (+) + + – – The dominate polar site reactivity (–) The typical behavior of nitronate anions 14 is summarized in the representative transformations provided in Scheme VI. These moderately nucleophilic species, although they are not readily alkylated, readily undergo aldol and conjugate addition reactions. + N O + N –O –O –O CH2–R CH–R + N O –O El + N O –O R CH–R + N O –O CH2–R Scheme VI Selected Reactions of the Nitronate Anion base pKa ~ 10 El(+) The Reaction: ● ● – The charge affinity pattern: (–) ■ This reactivity pattern may be extended via conjugation: It is no surprise that the charge affinity pattern of this FG may be extended by conjugation, and a,b-unsaturated nitro compounds readily participate in conjugate addition reactions (Scheme VII). R H N X: R H N X: R H N X: + N O –O CH CH R + N O –O CH2 CH Nu R + N O –O CH CH R + N –O –O CH CH R + N –O O Scheme VII Selected Reactions of the Nitronate Anion X = OR, NR2 (–) (–) (+) (+) ■ The resonance feature which has been exploited: Nu(–) (–) (+) The Reaction: The charge affinity pattern: (–) (+) + (+) (+) Nitro aromatics: (+) ✔✔

The non-alternate behavior of the nitro functional group is dramatically illustrated in the transfor ophilic i provided in Scheme VIll. In both instances the derived anions 16 and 17 are highly nucle- mation The non-alternate charge affinity patterns of these nucleophiles is provided Scheme vili Deprotonated Nitronate anions n-BuLi (-)(-) FG→C-C(9) 8°C tion, The nitro group also exhibits the potential of undergoing direct displacement under specific condi- ous literature precedents for this general class of reactions. 14 while table Il provides some of the cl er- tions, a general transformation characteristic of E-functions. a recent review by Tamura provides numer- actions. Although the NO2 group cannot be considered as a general leaving group, there are a number of conditions under which this moiety can be exploited, particularly when it is either allylic or tertiary (10) Table Ill. Representative Substitution Reactions of the Nitro Group(eq 10) NO. Pd(PPh3) CH(CO2Me)2 NaCH(CO2Me) Pd(PPh3)3 Me TiCl SO2 Ph 65% Nao, SPh Pd(PPh3h SPh a particularly useful transformation of the nitro group is the Nef Reaction, a process which trans forms NO2 into=O(Scheme IX). A recent comprehensive review of this transformation provides a detailed discussion of this process. 15 In addition to the Pinnick review, Seebach has also written a comprehensive eview of the diverse chemistry of the nitro functional group. 16 3)(a)Henning, R. Lehr, F; Seebach, D. Helv. Chim. Acta 1976, 59, 2213-2217;(b)Seebach,D,Henning, R.Lehr 14F. Gonnerman Tetrahedron lett. 1977,11610064 15) Pinnick,H Reactions1990,38,655-792 16) Seebach, D. Ce F Weller. T: Chimia 1979.33.1-18

Functional Group Classification page 7 The non-alternate behavior of the nitro functional group is dramatically illustrated in the transfor￾mations provided in Scheme VIII. In both instances the derived anions 16 and 17 are highly nucle￾ophilic.13 The non-alternate charge affinity patterns of these nucleophiles is provided. N O N O O C O C CH3 Li CH2Li CH3 N O O C CH3 H FG C N FG C C O O C CH3 CH3 17 16 Scheme VIII Deprotonated Nitronate Anions (–) (–) (–) (–) n-BuLi -78 °C (9) (8) -78 °C LDA – – + + – – – – + – – + The nitro group also exhibits the potential of undergoing direct displacement under specific condi￾tions, a general transformation characteristic of E-functions. A recent review by Tamura provides numer￾ous literature precedents for this general class of reactions.14 while table III provides some of the cited re￾actions. Although the NO2 group cannot be considered as a general leaving group, there are a number of conditions under which this moiety can be exploited, particularly when it is either allylic or tertiary. N O O CH R R Nu CH R R FG C – + Nu(–) (+) + NO (10) 2 – NO2 N H N(CH2 )5 CH(CO2Me)2 SO2Ph NO Ph 2 Ph Me Me SPh NO2 SiMe3 Me Me Me NO2 t-Bu OMe Me Me SPh Me Ph SPh NO2 Me Ph SPh CN Pd(PPh3)3 NaCH(CO2Me)2 NaO2SPh Pd(PPh3)3 Pd(PPh3)3 SnCl4 74% Anisole 94% SnCl4 TiCl4 65% 73% TiCl4 Me3SiCN Table III. Representative Substitution Reactions of the Nitro Group (eq 10). A particularly useful transformation of the nitro group is the Nef Reaction, a process which trans￾forms NO2 into =O (Scheme IX). A recent comprehensive review of this transformation provides a detailed discussion of this process.15 In addition to the Pinnick review, Seebach has also written a comprehensive review of the diverse chemistry of the nitro functional group.16 13) (a) Henning, R.; Lehr, F.; Seebach, D. Helv. Chim. Acta 1976, 59, 2213-2217; (b) Seebach, D.; Henning, R.; Lehr, F.; Gonnermann J. Tetrahedron Lett. 1977, 1161-1164. 14) Tamura, R.; Kamimura, A.; Ono, N. Synthesis 1991, 423-434. 15) Pinnick, H. W.; Org. Reactions 1990, 38, 655-792. 16) Seebach, D.; Colvin, E. W.; Lehr, F.; Weller, T.; Chimia 1979, 33, 1-18

Scheme lx the nef reaction Overall Transformation ■ Mechanlsm o nitronate anion nitronic acid x←吗 E-Property The Diazo Functional Group. This functional group provides one of the best illustrations of an A-function. As illustrated in Scheme X, both()and(+)polar site reactivity is observed in is reactions with carboxylic acids Scheme ix the nef reaction Overall transformation 1)HO- ■ Mechanisn HO nitronate anion nitronic acid E-Property Deman the same overall reactivity, pattern is expressed by the diazo functional group in the Tiffeneau- ov ring expansion reaction '7 wherein diazomethane functions as the nucleophilic agent in the first step and the functional group is lost as a leaving group in the subsequent step(Scheme XI) Scheme XI The Tiffeneau-Demyanov Ring Expansion Restriction: Starting ketone must be more reactive than product keton For a monograph on ring expansion reactions see: Hesse, M. Ring Enlargement in Organic Chemistry, VCH: New York. 1991

Functional Group Classification page 8 + N R R O – O H + N R O R R + N R HO – O R R O – O H + N R + N R R R – O – O HO HO N R R HO HO OH O R R N H H HO HO 1) HO – nitronate anion HO – H + ■ Overall Transformation: ■ Mechanism nitronic acid H + H2O - H + + Scheme IX The Nef Reaction G-Property E-Property The Diazo Functional Group. This functional group provides one of the best illustrations of an A-function. As illustrated in Scheme X, both (–) and (+) polar site reactivity is observed in is reactions with carboxylic acids. + N R R O – O H + N R O R R + N R HO – O R R O – O H + N R + N R R R – O – O HO HO N R R HO HO OH O R R N H H HO HO 1) HO – nitronate anion HO – H + ■ Overall Transformation: ■ Mechanism nitronic acid H + H2O - H + + Scheme IX The Nef Reaction G-Property E-Property The same overall reactivity pattern is expressed by the diazo functional group in the Tiffeneau￾Demjanov ring expansion reaction17 wherein diazomethane functions as the nucleophilic agent in the first step and the functional group is lost as a leaving group in the subsequent step (Scheme XI). O O HO CH2–N2 N2 C R N2 C R CH2N2 EtOH + (–) (+) Restriction: Starting ketone must be more reactive than product ketone Scheme XI The Tiffeneau-Demyanov Ring Expansion -N2 17) For a monograph on ring expansion reactions see: Hesse, M. Ring Enlargement in Organic Chemistry; VCH: New York, 1991

Sulfur-Based Functional Groups Sulfonium Salts. The dual electronic behavior of sulfur functi ly be illustrated in the reac- tions of sulfur ylids which are excellent examples of A-functions. As illustrated in Scheme Xll, sulfonium salts are effective in carbanion stabilization a characteristic of G-functions. and sulfonium salts are effective leaving groups, a characteristic of E-functions Scheme XIl. Sulfonium Salts: Modes of Reactivity Carbanion Stablization CH3 E R2s—C pKa(DMso)- 18 .eaving Group Potential: Good /S-CH3 Nu: 2 R2s The non-alternate reactivity pattern of trimethy sulfonium ylids is revealed in the cyclopropanation of unsaturated ketones as illustrated in the case below(Scheme XIII). 18 Scheme xiil. Reactions of Sulfonium Ylids: Conjugate Addition R2S→C R2S→C a Nonalternate reactivity pattern revealed in consecutive reactions Sulfones. Other types of sulfur-derived functional groups exhibit reactivity profiles similar to that exhibited by sulfonium salts. A number of excellent applications of the arylsulfonyl functional group illus trate this point. Two applications utilizing the sulfone functional groups are presented below The phenylsulfonyl moiety strongly stabilizes carbanions and may be equated with the -CN FG in its potential for hydrocarbon acidification. 19 In addition, this FG is a respectable leaving group in selected situations. In comparisons with sulfonium ions( Scheme XV), arylsulfonyl-stabilized carbanions are more nucleophilic than sulfonium ylids(G-property), while ArSO2-is a poorer leaving group than Me2S(E Property Scheme xv. Sulfones: Modes of Reactivity Ph BuLi more nucleophilic poorer leaving 一CH3 group than 18) Corey, E. J: Chaykovsky, M.J J.Am.Chem.Soc.1965,87,1352-1364 For an excellent compilation of pKa data for organic functional groups in DMSO see: Bordwell, F G. Acc. Chem. Res 1988,21,456-4

Functional Group Classification page 9 Sulfur-Based Functional Groups Sulfonium Salts. The dual electronic behavior of sulfur functions may be illustrated in the reac￾tions of sulfur ylids which are excellent examples of A-functions. As illustrated in Scheme XII, sulfonium salts are effective in carbanion stabilization, a characteristic of G-functions, and sulfonium salts are effective leaving groups, a characteristic of E-functions. S CH3 R R R2S C R2S C S CH3 R R S Me Nu R R S CH2 R R Scheme XII. Sulfonium Salts: Modes of Reactivity ●● – + H ■ Carbanion Stablization: + pKa (DMSO) ~ 18 ■ Leaving Group Potential: Good + SN 2 + + Nu: ●● + + (–) (+) The non-alternate reactivity pattern of trimethylsulfonium ylids is revealed in the cyclopropanation of unsaturated ketones as illustrated in the case below (Scheme XIII).18 O O – S Me Me O – S Me Me S CH2 Me Me O R2S C R2S C + ●● – Scheme XIII. Reactions of Sulfonium Ylids: Conjugate Addition (–) (+) + + (+) ■ Nonalternate reactivity pattern revealed in consecutive reactions Sulfones. Other types of sulfur-derived functional groups exhibit reactivity profiles similar to that exhibited by sulfonium salts. A number of excellent applications of the arylsulfonyl functional group illus￾trate this point. Two applications utilizing the sulfone functional groups are presented below. The phenylsufonyl moiety strongly stabilizes carbanions and may be equated with the –CN FG in its potential for hydrocarbon acidification.19 In addition, this FG is a respectable leaving group in selected situations. In comparisons with sulfonium ions (Scheme XV), arylsulfonyl-stabilized carbanions are more nucleophilic than sulfonium ylids (G-property), while ArSO2- is a poorer leaving group than Me2S- (E￾Property). Me S Me Ph O O Li S CH2 R R Me S Me Ph O O S CH3 R R Me S Me Ph O O pKa ~ 25 BuLi more nucleophilic than: + ●● – poorer leaving group than: + Scheme XV. Sulfones: Modes of Reactivity 18) Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1965, 87, 1352-1364. 19) For an excellent compilation of pKa data for organic functional groups in DMSO see: Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456-463