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chapter 2 Acids, Bases and Functional Group Exchange eactions 2.1. Introduction In most syntheses, the main focus is usually on construction of the molecule using carboncarbon bond forming reactions. Most
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chapter 2 Acids, Bases and Functional Group Exchange eactions 2.1. Introduction In most syntheses, the main focus is usually on construction of the molecule using carboncarbon bond forming reactions. Most of the actual chemical reactions in a synthesis, however, are those that incorporate or change functional groups. Such reactions are known as functional group exchange reactions, and this chapter will review major reaction types involved in functional group exchanges. For all practical purposes, this discussion also constitutes a review of a typical undergraduate organic course. Figure 1.1 showed that many functional group interchange reactions are chemically related. These transformations usually proceed via ionic intermediates and/or polarized C-X bonds, or they involve π bonds. A short list of typical reagents was provided in that Figure, but many other reagents are usually available to effect a given transformation. Functional group exchange reactions generally have two functions in syntheses. Functional groups are (1) a structural feature of the final target, and (2) a necessary feature incorporated into a molecule that must be manipulated (transformed) to alter or form a carbon-carbon bond. Functional group interchange reactions are, therefore, very important in synthetic organic chemistry. Many different types of reactions are used in functional group interchanges. We can categorize reactions according to the type of transformation, which is a subset of functional group interchanges. This categorization can help us understand when and how to use a particular reaction. Grouping reactions by similar or related mechanisms is very common. 1.LiAl4 2 1 K 2, P 3 4 Et 5 2 The importance of functional group exchange reactions is illustrated by a simple synthetic problem, in which bromohydrin 2 is prepared from cyclohexanone (1). This particular synthesis chapter 2 77 requires only functional group transformations. The synthetic relationship between 1 and 2 is represented in the diagram as 2 1, which is meant to show that the bromohydrin can be formed from the ketone by an as yet unknown number of synthetic steps. Corey and co-workers 1,2 called this representation a transform, and used it to define retrosynthetic relationships (sec. 1.2). If we analyze the 2 1 relationship, it is clear that and must be incorporated on adjacent carbons, and one possibility is an addition reaction to an alkene. We must somehow convert the ketone to an alkene. ne approach would involve reduction of the carbonyl to an alcohol, which could be converted to a leaving group that would allow an elimination reaction to give the alkene. This analysis is based on the synthetic conversion of 1 to 2, and the reaction types suggested by this analysis leads to a choice of the reagents that are required for each transformation. Initial reduction of the ketone, with a suitable reducing agent such as LiAl 4 (sec. 4.2.B) gives alcohol 3. Subsequent reaction with phosphorus tribromide (sec. 2.8.A) gives bromide 4, in what is known as a substitution reaction. Base induced elimination gives alkene 5, which illustrates both elimination and an acid-base reaction. The final reaction with bromine and water (sec C) gives 2, and illustrates an addition reaction. This sequence used five major reaction types: acid-base, reduction, substitution, elimination, and addition. Te reaction types used for functional group exchanges are collected into seven traditional categories: 1. Acid - base reactions A + B B + A 2. Substitution reactions X + A A + X 3. Elimination reactions X-C-C-Y C=C + X-Y 4. Addition reactions C=C + X-X X-C-C-X 5. ucleophilic acyl addition C= uc-c--e 6. xidation reactions An example is -C-- C= 7. eduction reactions An example is C=C -C-C- Most functional group exchanges and transformations fall into one of these seven categories, which it is useful for classification of reagents, as in Table Many reactions can be placed into more than one of these simple categories. Elimination reactions, for example, involve an initial removal of hydrogen by a base (an acid-base reaction). Addition reactions are twostep reactions that involve a substitution. xidation and reduction reactions constitute such a large proportion of functional group exchanges that they will be discussed in separate chapters (chaps. 3 and 4, respectively), to properly examine their synthetic applications. This chapter 1. Corey, E.J.; Cheng, X. The Logic of Chemical Synthesis, Wiley Interscience, ew York, (a) Corey, E.J.; Wipke, W.T. Science, 1969, 166, 178; (b) Corey, E.J.; Long, A.K.; ubinstein, S.D. Ibid 1985, 228, 408; (c) Corey, E.J.; owe, W.J.; Pensak, D.A. J. Am. Chem. Soc. 1974, 96, 7724; (d) Corey, E.J. Quart. ev. Chem. Soc. 1971, 25, 455; (e) Corey, E.J.; Wipke, W.T.; Cramer, III,.D.; owe, W.J. J. Am. Chem. Soc. 1972, 94, 421; (f) Corey, E.J.; Jorgensen, W.L. Ibid 1976, 98, Many examples of these types of reactions are found in Larock,.C. Comprehensive rganic Transformations, 2nd Ed. Wiley-VC, ew York, chapter 2 78 will begin with the first five reaction types to discuss their application to chemical reactions, synthesis, and functional group transformations. The ultimate goal is to establish a firm base upon which to introduce both the reactions required for making important carbon-carbon bonds, and also the techniques employed by the modern synthetic chemist. Substitution (S 1 or S 2) is a reaction where one functional group attached to n aliphatic carbon is replaced by another called a nucleophile (nucleophilic aliphatic substitution). ucleophiles can also form a new bond to an acyl carbon (nucleophilic acyl addition). Both of these retrosynthetic transforms are represented by the C-uc species, where uc = C, Ac,, 3, C 2, etc. and X = Cl,, I, Ac, S 2, etc., for S 2 reactions. In nucleophilic acyl substitutions, the nucleophile is usually a carbon, nitrogen or oxygen species. C uc C X uc = nucleophile C uc nucleophilic aliphatic substitution C nucleophilic acyl substitution Table 2.1. Correlation of Common eagents with General eaction Types Class of eagent (eaction Type) eagents Acids ( acid-base; addition) Cl,, F, I, 2 S 4, 3, 3 P 4, C 2, S 3,,, AlX 3, FeX 3, ZnX 2, SnX 4 Bases (acid-base; elimination) a, K, Li, Ca() 2, a, K, M+ (t- Bu,, Et; M = a+, K+), Li, MgX, 3, 3, a 2, Li 2, a 2 or Li 2 ( 2 + a or Li),,, ucleophiles (substitution; nucleophilic MX (X=Cl,, I, C ),,, 2, 2, acyl substitution) C X, (C), S, S ; M=a +, K +, Li +, Li, MgX, 3, 3,,, 2 CuLi xidizing agents (oxidation; addition; acid-base) educing agents (reduction; addition) Cr 3, K 2 Cr 2 7, 2,, Cr 4, KMn 4, Cu/heat, Mn 2, Se 2, I 4, 3, ax(a/x 2 ), BS, CS, C 3, (a 2 /X), 3, 2 S 4, Ag + +, Cu 2 Sn/Cl, Fe/Cl, 2 + catalyst, (Pd, Pt, i(), u), ab 4 (=, alkyl, ), LiAl 4 (=, alkyl, ) eagents that are classified as bases can be used with both Lewis and ønsted-lowry acids, and one application is the elimination of alkyl halides (E2 reactions; sec. 2.9.A) in the presence of a base. Elimination involves conversion of a saturated moiety containing a leaving group to chapter 2 79 a molecule with a multiple bond. An example of this latter transform is: C C C C X elimination where the leaving group (X) is, halogen, Ts, and so on. The E2 reaction is discussed in section 2.9.A. ote that another class of elimination reactions includes polar species such as sulfoxides, amine oxides, and selenoxides, which undergo thermal syn elimination (sec. 2.9.C). Acid-base reactions are among the most general that are known. They are used to generate reactive intermediates that can be part of other reaction types. Both Lewis and ønsted-lowry bases donate two electrons to an acid. Acid-base reactions are integral to many reactions, although they are not always easy to describe by a specific transform since they may be an adjunct to the desired transformation. An example is the use of conjugate bases of acids as nucleophiles in substitution reactions. Typical reactions that generate nucleophiles are C C and 3 3. Conjugate bases of weak acids are usually required to initiate E2 type reactions, and typical examples are ethoxide and amide bases from the reactions Et Et and Et 2 LiEt 2. Many reagents that add to alkenes are acids (Cl,, etc.), and the reaction mechanism for these reactions begins with the alkene reacting as a base, donating two electrons to the acid ( + ). Addition reactions involve the transformation of sp hybridized carbons to sp 2 or to sp 3, or the transformation of sp 2 hybridized carbon atoms to sp 3. Addition reactions that add strong protonic acids X, or diatomic bromine, chlorine, etc. to alkenes, are common in synthesis. The retrosynthetic transform can be generalized as: X C Y C C C X C Y C C C As each of these reaction types is discussed in later sections, it will be apparent that virtually all substrates that are functionally transformed are polarized or contain π bonds. Pericyclic reactions will be presented in Chapter 11, and are an important exception. When analyzing a substrate for a functional group transform, the following criteria are usually important. 1. Examine the degree and direction of polarization of a bond. Where will the electrons go? 2. ow many bonds away will the polarization be effective? 3. What is the attraction of a given reagent for the polarized bond? 4. Does the polarized bond contain more than one leaving group. 5. If there is a π bond, how efficiently can it donate electrons. chapter 2 80 6. If the π bond is polarized, will the δ+ center undergo substitution or will the δ- pole act as an electron donor. 7. Does the reactive center possess special strain or steric hindrance that will modify the reactivity? 8. Is the reactive center conjugated? Perhaps most importantly, 9. Is there more than one reactive center in the molecule and can more than one reaction occur competitively? 2.2. ønsted-lowry acids and bases Many organic molecules react via an initial acid-base reaction that is formally classified by a ønsted-lowry definition. emember that a ønsted-lowry acid is a proton donor and a ønsted-lowry base is a proton acceptor. The key to this definition is an understanding that there is a proton transfer and change the focus to understand that a base removes the proton from the acid by donating two electrons to the proton. We are therefore looking for proton donors and acceptors, and specifically for molecules that donate electrons to a protonic acid to form a new bond to that hydrogen atom. Understanding the properties of acid-base equilibria is an aid to understanding the mechanistic details of many different reactions. 2.2.A. Acidity in rganic Molecules The reaction of A and B to give B + and A is the general expression written for acid-base reactions. The acid (A) reacts with a base (B:) to give the conjugate acid B + (CA) and a conjugate base, A (CB). The hydrogen atom is transferred to B: as a proton (+ ). Since the product B + is also an acid and A is a base, they react to establish an equilibrium. The position of the equilibrium is given by the equilibrium constant K, where K a is used for acidbase reactions. A small value of K a represents little ionization of A, which means that the equilibrium is shifted to the left and this shift is associated with decrease in the acidity of A. In other words, if the equilibrium lies to the left, A did not react with the base (B) to any great extent and it is considered to be a weaker acid. If K a is large, A reacted with B to produce B + and A, so the equilibrium is shifted to the right and A is considered to be a stronger acid. The position of the equilibrium is dependent on many factors, including the solvent. A more convenient way to express the relative strength of an acid is pk a. A large K a is equivalent to a small pka so as the pk a decreases, the acid strength increases. ote that our definition of a strong acid (large K a ) implies that the reaction of A and B is more facile than the reverse reaction of B + and A. Conversely, a weak acid (small K a ) implies that the reaction of B + and A is more facile than that of A and B. chapter 2 81 K a A + B B + + A [B + ] [A ] K z = where pk a = log k a and [A] [B:] pk a K = 10 Many organic compounds such as carboxylic acids, phenols and 1,3-dicarbonyl compounds are acids, but they are typically much weaker than the familiar mineral acids Cl or 2 S 4. Likewise, many organic compounds (particularly amines and phosphines) are bases, but such bases are generally weaker than alkali bases such as a. Amphoteric compounds such as alcohols are common. Alcohols are weak acids in the presence of a strong base, but they are weak bases in the presence of a strong acid. This chemical reactivity can be exploited in many chemical transformations. In the reaction of 3-pentanol (6) and + (Cl), the initial product is oxonium ion (7). elating this reaction to the generic acid-base reaction shown above [A] is the acid catalyst (Cl), [B] is the oxygen atom of 3-pentanol, the chloride ion is [A ] (the gegenion of the acid catalyst), and [B + ] is Et 2 C- 2 + (7). An acid catalyst that is strong enough to react with the alcohol, which is a weak base, initiates the reaction. In other words, the acid catalyst must be a stronger acid than the unit of the alcohol. In this particular reaction 7 is formed and reacts with the nucleophilic chloride ion at carbon, with loss of the leaving group water to give 3-chloropentane as the final product. 6 Cl Cl Cl Ethers are weak bases. Although they are commonly used as solvents, diethyl ether and TF are weak bases in the presence of a strong acid and TF is a stronger base than diethyl ether. The relative base strength can be seen upon examination of the experimentally determined acidity of the conjugate acid derived from diethyl ether [Et 2 + ], which has a pk a = This acid is stronger than the protonated form of TF [C ], which has a pk a = In reactions where the ether behaves as a Lewis base, as in Grignard reactions (sec. 8.4.A) or hydroboration (sec. 5.2.A), understanding the relative basicity is important. The hydrogen on the α-carbon of a ketone such as 2-butanone is an important weak acid in organic chemistry. When 2-butanone (A) reacts with sodium ethoxide (B), the conjugate base is enolate anion 8 (CB), and ethanol is the conjugate acid (CA). Ethanol (pk a about 17) is a stronger acid than the ketone (pk a about 19-20) and will react with the basic enolate to regenerate the ketone and shift the equilibrium back to the left. The net result is an equilibrium 4. (a) Arnett, E.M.; Wu, C.Y. J. Am. Chem. Soc. 1960, 82, 4999; (b) Arnett, E.M.; Wu, C.Y. Ibid 1962, 84, 1680, 1684; (c) Deno,.C.; Turner, J.. J. rg. Chem. 1966, 31, chapter 2 82 solution that contains enolate 8, ethanol, 2-butanone, and aet (sec. 9.2.E). 5 It is important to note that in any acid-base reaction, A does not function as a ønsted-lowry acid unless a sufficiently strong base (B) is present to remove and accept the acidic proton. If the base under consideration is too weak, the equilibrium is shifted almost exclusively to the left (i.e., we call A a weak acid). [A] + aet [B] [CB] 8 a + + Et [CA] When comparing two acids, several factors can be used to evaluate relative acid strength. In an acid-base reaction where acids are on both sides of the equilibrium (A and CA from above), this information can be useful to estimate the position of the equilibrium, which is essentially an estimation of K a. 1. In general, a strong acid generates a weak conjugate base and, conversely, a weak acid generates a strong conjugate base. Comparison of Cl and 3 indicates that Cl is a strong acid that generates the weak base, Cl : Cl + + Cl Conversely, ammonia is a weak acid that generates the strong base, Cl A base will usually deprotonate an acid that has a pk a lower than its own conjugated acid, and the extent to which the reaction produces products if the main criterion for labeling a base as strong or weak. 2. Across the periodic table, acidity of an X- species generally increases from left to right. 6 weak acid C4 3 2 F strong acid pk a ( 50) ( 31) (15.7) (3.17) strong conj. base C 3 2 F weak conj. base 5. (a) ouse,.. Modern Synthetic eactions, 2nd Ed. W.A. Benjamin, 1972, pp ; (b) ouse,..; Phillips, W.V.; Sayer, T.S.B.; Yau, C.C. J. rg. Chem. 1978, 43, 700; (c) Etheredge, S.J. Ibid 1966, 31, 1990; (d) ouse,..; Czuba, L.J.; Gall, M.; lmstead,.d. Ibid 1969, 34, 2324; (e) ouse,..; Gall, M.; Almstead,.D. Ibid 1971, 36, Lowry, T..; ichardson, K.S. chanism and Theory in rganic Chemistry, 3rd Ed. arper and ow, ew York, 1987, pp chapter 2 83 A consequence of this trend in acidity is that basicity increases from right to left across the periodic table. 3. Acidity increases going down the periodic table, despite a decrease in electronegativity. F (3.17) Cl ( 7) ( 9) I ( 10) 7 and, 2 (15.74) 2 S (7.00) 6 Based on rule 3, basicity increases going up the periodic table. Fluoride is smaller and more electronegative than iodide, has a greater attraction for protons, and forms a stronger covalent bond. These factors make it more difficult to lose a proton from F than from I, hence, the equilibrium is shifted to the left relative to I, and F is a weaker acid. Clearly, the increased size of the iodine atom leads to a greater -I bond distance and, due to the resultant decrease in internuclear electron density, a weaker bond. The acid strength increases, since the weaker I- bond is more easily ionized, which ignores solvation effects, however, as well as product stability, which are critical to this analysis (see below). owever, we must look at the both the starting materials and the products to determine the position of the equilibrium, and thereby the relative acidity. The iodide ion is larger than the fluoride ion and the charge is dispersed to a great extent, leading to greater stability. The larger ions are also more easily solvated, again leading to greater stability. Greater stability of one product relative to the other means the equilibrium is shifted further to the right for I-iodide, and this leads to I being a stronger acid. These three concepts allow a quick inspection of a simple acid (X) for its relative acid strength. Experimental analysis of the acids commonly encountered in organic reactions requires knowledge of at least three factors: (1) electronic effects, (2) resonance effects, and (3) solvent effects. The presence of an electron-donating or an electron-withdrawing heteroatom (or group) on a carbon induces bond polarization through adjacent carbon atoms in a chain, as illustrated by 9 (first introduced in section 1.3). 8 Electron-donating groups release electrons via inductive or field effects, leading to the so-called +I effect. Conversely, an electron-withdrawing group removes electron density, the so-called I effect. With respect to an acid, the +I effect lowers the acid strength whereas the I effect raises it. Electronic effects are described by the inductive model 9,10 and the field effect model. 9,11 7. Smith, M.B.; March, J. March s Advanced rganic Chemistry, 6th ed.; Wiley, ew York, 2007, pp 384, (a) Seebach, D. Angew. Chem. Int. Ed. 1979, 18, 239; (b) Cram, D.J.; Cram, J.M. Chem. Forsch. 1972, 31, 1 [Chem. Abstr. 77:163690d 1972]. 9. (a) Baker, F.W.; Parish,.C.; Stock, L.M. J. Am. Chem. Soc. 1967, 89, 5677, (b) Golden,.; Stock, L.M. Ibid , 5928, (c) oltz,.d.; Stock, L.M. Ibid 1964, 86, anch, G.E.K; Calvin, M., The Theory of rganic Chemistry, Prentice all, ew York, 1941, Chapter (a) Kirkwood, J.G.; Westheimer, F.. J. Chem. Phys. 1938, 6, 506; (b) Westheimer, F..; Kirkwood, J.G. Ibid 1938, 6, 513. chapter 2 84 The inductive model assumes that substituent effects are propagated by the successive polarization of the bonds between the substituent and the reaction site (as in 9). This effect is transmitted through the σ bond network (σ inductive effect) as well as the π-bond network (π i
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