哈佛大学：《高等有机化学》课程教材讲义（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 (+–)