CHAPTER OUTLINE

  6.1   Introduction

  6.2   Nucleophiles

  6.3   Electrophiles

          Box 6.1—Electrophiles in cancer drugs

  6.4   Leaving Groups

  6.5   Nucleophilic Aliphatic Substitution Reactions—S_N2

          Box 6.2—S_N2 reactions in biological chemistry

  6.6   Nucleophilic Aliphatic Substitution Reactions—S_N1

  6.7   Neighboring Group Assistance in S_N1 Reactions

  6.8   Nucleophilic Aromatic Substitution Reactions—S_NAr

  6.9   Addition reactions

6.10   Elimination Reactions—E1 and E2

6.11   Summary

6.12   Case Study—Drugs That Form a Covalent Bond to Their Target

6.13   Exercises

6.1 Introduction

The first few chapters of this text were focused on important properties of organic molecules and how these help determine the nature of a drug’s interaction with its biological target. In this chapter and the ones that follow, we will discuss certain reactions of drug molecules and enzymes – biological macromolecules that break and form chemical bonds. In this chapter we discuss substitution, addition, and elimination reactions. The main focus is on substitution reactions, which are prevalent in physiological and metabolic processes, in the action of some drugs, and in the chemical synthesis of nearly all drugs. The topic of addition reactions is introduced here and expanded upon in the following chapter on carbonyl chemistry.

Substitution reactions involve the reaction of nucleophiles with electrophiles. Nucleophiles are “nucleus seekers” that will donate a lone pair of electrons to the new bond that is formed with an electrophile. Electrophiles are “electron seekers” and thus accept a lone pair of electrons from a nucleophile. Some examples of nucleophiles and electrophiles are shown in Figure 6.1. Nucleophiles generally are anionic or neutral with a lone pair of electrons to donate. Electrophiles are positively charged or have a polarized bond with partial positive character. Electrophiles capable of undergoing substitution reactions have a leaving group, a species that can accept and stabilize the pair of electrons that make up the bond being broken.

Figure 6.1 Examples of some good nucleophiles, electrophiles, and leaving groups.

In the sections that follow, we will discuss in more detail the factors that make for a good nucleophile, electrophile, or leaving group. We will also review the various reaction mechanisms by which substitution, addition, and elimination reactions occur. By the end of the chapter you should have developed a sound understanding of the factors that govern these reactions and be able to predict reaction products when provided with the reactants and reaction conditions. You should also be able to write reasonable mechanisms for your reactions, making the proper use of curly arrows to show the movement of electrons as chemical bonds are formed and broken.

6.2 Nucleophiles

In the previous chapter, we used the Brønsted–Lowry definition of acids and bases—species that donate or accept a proton, respectively. A more general description of acids and bases is that first proposed by the chemist Gilbert N. Lewis, who described a covalent bond as the sharing of an electron pair between two atoms. Thus, a Lewis acid is a species that can accept an electron pair and a Lewis base is a species that can donate an electron pair in the formation of a covalent bond. A proton (H⁺) qualifies as a species that can accept a lone pair of electrons and thus the Lewis description of acids and bases encompasses the Brønsted–Lowry definition. However, Lewis’ definition is more general and thus useful also to describe the reactions of nucleophiles and electrophiles (Figure 6.2). For example, we can say that a nucleophile acts as a Lewis base when it donates an electron pair in reaction with an electrophile (a Lewis acid) that accepts the electron pair. While acid-base reactions involve transfer of electrophilic protons, nucleophilic addition and substitution reactions involve a much broader range of electrophiles, as can be seen later in this chapter.

Figure 6.2 An acid-base equilibrium (top) shares many aspects of a nucleophilic substitution reaction (bottom). Both reactions involve species that donate an electron lone pair (Lewis bases, B: and Nu:) and species that accept an electron lone pair (Lewis acids, H–A and E–L).

When describing nucleophilic substitution reactions, the term nucleophilicity is often used to describe the relative strength of a nucleophile—its ability to donate electrons. Table 6.1 compares the relative reactivity of a variety of common nucleophiles. What is apparent immediately is that most good nucleophiles in the table are anionic. This makes sense given that anionic species have an abundance of electrons. Now let us consider the four anionic species below derived from C, N, O, and F, which are immediately adjacent to one another in the second row of the periodic table. In this series of anions nucleophilicity decreases from left to right, with the methyl anion the strongest nucleophile, followed by the amide anion, hydroxide anion, and finally fluoride anion.

Table 6.1 Nucleophilicity of Some Common Nucleophiles.

This trend can be readily understood by considering the electronegativity of the atoms. Each anion possesses a full octet of valence electrons and a formal –1 charge, while the number of protons in the nucleus increases in the order C (6), N (7), O (8), F (9). Thus, proton-abundant and electronegative fluorine holds its electrons very tightly, making fluoride the least nucleophilic anion in the series. This trend in nucleophilicity is also correlated with the relative basicity of the anions, methyl anion being the strongest base and fluoride the weakest. Recall that weak bases have relatively little affinity for protons, and we might expect them to have low affinity for other electrophiles as well. However, other factors can muddy the relationship between basicity and nucleophilicity, as in the case of the halides.

The halide anions iodide, bromide, chloride, and fluoride are nucleophilic anions from the same column or “group” of the periodic table. As in the previous case, nucleophilicity in this series is correlated with electronegativity and the order of relative nucleophilicity is that shown below.

However, if we consider the relative acidity of the corresponding conjugate acids we find the order to be HI > HBr > HCl > HF. Thus, the trend with respect to basicity is opposite from what we might have predicted—the weakest base, iodide, is the best nucleophile. Why should the weakest base (the least proton-seeking) be the most nucleophilic (most nucleus-seeking)? The answer is related to the fact that basicity is a measure of affinity for protons, whereas nucleophilicity is more a measure of affinity for carbon-based electrophiles. In reactions with carbon electrophiles, the polarizability of the nucleophile is an important factor. Among the halide anions, iodide is the largest in size and its nucleus is least able to attract its outermost valence electrons. The highly polarizable iodide anion is most nucleophilic because it is most likely to react with the more diffuse positive charge that is characteristic of carbon electrophiles. At the other extreme in terms of polarizability is fluoride. Smallest in size and with its valence electrons held close to the nucleus, the electron cloud of fluoride is not at all polarizable and thus least reactive with carbon electrophiles.

The relationship between basicity and nucleophilicity may be further refined by a brief introduction to hard-soft acid base (HSAB) theory. In HSAB theory a “hard” acid or base is a species with very little polarizability—think of a proton (a very hard acid) or fluoride anion (a very hard base). A “soft” acid or base then is a species with high polarizability and a more diffuse distribution of positive or negative charge. HSAB theory predicts that a hard base (or hard nucleophile) will prefer to react with a hard acid (or hard electrophile). Similarly, soft bases/nucleophiles will prefer to form bonds with soft acids/electrophiles. Using this concept we can understand how hydroiodic acid (HI) can be a strong acid while at the same time the iodide anion is a good nucleophile. In the molecule HI, the very hard proton is a poor match for the soft iodide anion. As a result, the covalent bond in HI is weak and prone to dissociate into ionic species in water (into H₃O⁺ and I ions), thus making HI a strong acid. However, in substitution reactions with carbon-based (soft) electrophiles, HSAB theory predicts the soft iodide anion will be a good reaction partner and thus a good nucleophile.

Nucleophilicity is also affected by the presence of electron withdrawing or donating substituents that interact with the nucleophilic atom via inductive or resonance effects. This is illustrated below for substitutions on a pyridine ring (Figure 6.3). The ring nitrogen atom of pyridine is nucleophilic on account of this atom having a lone pair of electrons to donate. The presence of a para-dimethylamino group on the pyridine ring will be electron donating through resonance and this will produce a much more nucleophilic pyridine species. Conversely, an ortho-fluoro substituent will be electron withdrawing by an inductive effect, resulting in a much less nucleophilic pyridine species. For ionizable groups such as the –OH function in phenol, it is important to consider the concentrations of both the neutral and anionic forms. With a pK_a ~10, phenol exists primarily in its neutral form at physiological pH. The introduction of electron-withdrawing substituents may well increase nucleophilicity under physiological conditions, since the effect will be to lower the pK_a and increase concentrations of the more nucleophilic phenoxide species.

Figure 6.3 Relative nucleophilicity of substituted pyridines (top) and of phenol in its protonated and deprotonated forms.

Nucleophilic sulfur, nitrogen, and oxygen atoms in the side chains of amino acids play essential roles in various biological processes. Specific cysteine (R–SH) and serine (R–OH) residues in the active sites of cysteine and serine proteases serve as strong nucleophiles, reacting with the electrophilic amide (peptide) bonds of their protein substrates. Methylation and acetylation of specific lysine side-chain amines in histones is crucial for the regulation of gene expression. Phosphorylation of specific serine, threonine, or tyrosine hydroxyl (–OH) groups by kinases represents one of the most important mechanisms of controlling protein function and signaling in biology. The thiol containing tripeptide glutathione is sometimes referred to as the “guardian of the cell,” on account of its various roles as an antioxidant and a nucleophilic scavenger of potentially harmful electrophilic species. Glutathione is activated by the enzyme glutathione S-transferase, which functions to activate the thiol function (R–SH) for nucleophilic attack on electrophilic substrates (Figure 6.4). When the substrate is a xenobiotic small molecule, the effect of reaction with GSH is to produce a water-soluble product, thus promoting excretion and protecting the cell or organism from the potentially toxic effects of the xenobiotic agent. The role of GSH in drug metabolism will be discussed in more detail in Chapter 8.

Figure 6.4 Reaction of the tripeptide glutathione with cellular electrophiles is promoted by the enzyme glutathione S-transferase.

6.3 Electrophiles

Electrophiles are Lewis acids—species that accept an electron pair in the formation of a new covalent bond. Electrophiles can carry a formal positive charge or can be neutral overall but with partial positive charge at specific electrophilic sites. We will be most concerned with carbon-based electrophiles since these species are of greatest relevance in organic chemistry and in the chemistry of biological molecules and drugs. As illustrated in Figure 6.5, electrophilic sites in organic molecules can occur at both saturated and unsaturated carbon centers. The focus of this chapter is on saturated carbon electrophiles, electrophilic C–C double bonds, and aromatic systems. The reactions of electrophilic C=O double bonds (carbonyl species) are the topic of Chapter 7.

Figure 6.5 Examples of both saturated and unsaturated carbon-based electrophiles. Electrophilic sites are those sites possessing partial positive character, shown in blue.

Let us now consider what makes the compounds in Figure 6.5 good electrophiles. Most obvious perhaps is the polarization of a C–X or C=X bond, producing a partial positive charge at one or more site(s) in the molecule. However, not all polarized C–X bonds are good electrophiles for substitution reactions. A perfect example of this is the C–F bond, which is highly polarized (fluorine being most electronegative element) and yet not particularly reactive with nucleophiles. One reason for this poor reactivity is that the C–F bond, while highly polarized, is also a very strong bond. A second reason is that fluoride is a relatively poor leaving group (the topic of Section 6.4). This highlights the fact that in any nucleophilic addition or substitution reaction, certain bonds must be broken even as others are being formed. Hence, a good electrophile will possess a relatively weak bond to a good leaving group. An example of such a molecule is methyl bromide (CH₃–Br), with its relatively weak C–Br bond to a good leaving group (Br). Epoxides are often good electrophiles because of their relatively weak and polarized C–O bonds, ring strain that is relieved upon breaking the C–O bond, and a reactive carbon atom that is sterically unhindered. Some examples of electrophilic chemotherapeutic agents are provided in Box 6.1.

Unsaturated sp² or sp-hybridized carbon atoms are generally poor electrophiles, except when directly bound to more electronegative atom, as is the case in the carbonyl (C=O) and nitrile (C≡N) functional groups. The reactivity of the carbonyl function is further impacted by the electronic and steric nature of the other substituent on the carbon atom (Figure 6.6 and Chapter 7). When a nucleophile reacts with a C=O bond, a tetrahedral intermediate is formed in which the negative charge is borne and stabilized by the electronegative oxygen atom. Similar reaction of a C=C double bond would place an unstabilized negative charge on carbon and thus simple C=C bonds are poor electrophiles. C=C double bonds can be rendered more electrophilic when they are substituted with one or more electron-withdrawing groups (EWG, Figure 6.5). Addition reactions of this type are covered in Section 6.9.

Figure 6.6 Relative reactivity of common carbonyl-containing electrophiles toward nucleophilic addition. The reactions of carbonyl species are more fully explored in Chapter 7.

6.4 Leaving Groups

Substitution or elimination reactions involve breaking of a bond to a leaving group. If the breaking bond is C–Br, the leaving group is the bromide anion, which accepts the pair of electrons that formed the C–Br bond. The rates and mechanisms of substitution and elimination reactions are thus dependent on the ability of the leaving group to accept an electron pair from the breaking bond. Good leaving groups are able to accept the electron pair and stabilize the resulting negative charge. Recall from the previous chapter that the conjugate base of a strong acid effectively stabilizes a negative charge and so such weak bases are generally good leaving groups. This relationship between basicity and leaving group ability is apparent with the halides, where iodide is both the weakest base and the best leaving group (Figure 6.7).

Figure 6.7 Leaving group ability is correlated with the ability to stabilize a negative charge and thus is related to basicity. A good leaving group is a weak base—the conjugate base of a strong acid.

Basicity and the ability to stabilize a negative charge are determined by various factors, including inductive effects, resonance effects, and polarizability. The relative basicity of the halides is significantly impacted by the relative polarizability (“hardness”) of the halide anion. Resonance and inductive effects are more dominant in the case of acetate and sulfonate anions, conjugate bases of acetic and sulfonic acids (Figure 6.8). Considering the acetate and trifluoroacetate anions, we might draw two resonance forms to show that the negative charge is shared equally by the two oxygen atoms, thus stabilizing the negative charge. What makes trifluoroacetate a much better leaving group (and a weaker base) is the strongly electron-withdrawing inductive effect of the trifluoromethyl group. The methane sulfonate anion (mesylate) is a better leaving group than either of the acetate anions because the negative charge is shared between three electronegative oxygen atoms (rather than just two). Better still is the trifluoromethylsulfonate anion (triflate), which combines stabilizing inductive and resonance effects and is one of the best leaving groups known.

Figure 6.8 Relative rates of a solvolysis reaction involving acetate and sulfonate anions as leaving group. Resonance and inductive effects combine to make the triflate anion an exceptionally good leaving group.

The reaction conditions employed in a substitution or elimination reaction can have a substantial effect on leaving group ability. For example, simple alcohols (R–OH) and amines (R–NH₂) are generally not reactive as electrophiles in substitution reactions since the hydroxide (OH) and amide (NH₂) anions are very poor leaving groups (they are strong bases). However, if the reaction is carried out under sufficiently acidic conditions these groups will become protonated to yield species like R–OH₂⁺ and R–NH₃⁺. Now the relevant leaving groups are the neutral species H₂O and NH₃, both weak bases and thus reasonably good leaving groups.

6.5 Nucleophilic Aliphatic Substitution Reactions—S_N2

The first type of substitution reaction we discuss in detail is the bimolecular nucleophilic substitution reaction, or S_N2 reaction for short. Two examples of S_N2 processes are shown in Figure 6.9. In the first reaction, hydroxide anion (HO) is the nucleophile, methyl bromide is the electrophile and bromide anion is the leaving group. Experimentally, the rate of this reaction can be shown to obey a second-order rate law, Rate = k[HO⁻][CH₃Br]. This rate law tells us that the nucleophile and electrophile are involved in a bimolecular reaction that is rate determining. The reaction occurs in a single step with the new C–O bond forming at the same time the C–Br bond is breaking (Figure 6.10). We say that S_N2 reactions are concerted processes since bond formation and bond breaking occur simultaneously. Another characteristic of an S_N2 reaction is inversion of stereochemical configuration at the carbon atom undergoing reaction. This is illustrated in Figure 6.9 for the case of an S_N2 reaction involving one enantiomer of a chiral alkyl bromide.

Figure 6.9 Examples of nucleophilic substitution reactions. Inversion of configuration as in the example at bottom is characteristic of the bimolecular nucleophilic substitution (S_N2) reaction.

Figure 6.10 The S_N2 mechanism of nucleophilic substitution. (Reproduced, with permission, from Carey FA, Giuliano RM. Organic Chemistry. 9th ed. New York: McGraw-Hill Education; 2014.)

If we inspect a potential energy diagram of the S_N2 reaction we see that there are no intermediates formed along the reaction coordinate, only a single transition state whose energy corresponds to the activation energy of the reaction (Figure 6.11). The structure of the transition state also reveals why S_N2 reactions proceed with inversion of configuration. The hydroxide nucleophile attacks the carbon electrophile along the axis of the C–Br bond, a trajectory often refered to as backside attack. To accommodate a bond at this position, the other three substituents on carbon must invert, much as an umbrella turns inside out when hit by a strong gust of wind.

Figure 6.11 Potential energy diagram describing the one-step biomolecular S_N2 reaction of hydroxide anion with methyl bromide. (Reproduced, with permission, from Carey FA, Giuliano RM. Organic Chemistry. 9th ed. New York: McGraw-Hill Education; 2014.)

An example of a concerted S_N2 reaction involving backside attack and inversion of configuration is the reaction of S-2-bromobutane with nucleophilic azide (Figure 6.12). Note that while configuration will always invert upon S_N2 reaction at a chirality center, the actual CIP desination (R or S) at the reaction center may or may not change, depending on CIP priority rules and the nature of the nucleophile and leaving group. The necessary inversion of configuration for an S_N2 process makes this reaction a stereospecific one (i.e., it affords a single stereoisomeric product that can be predicted based on the reaction mechanism).

Figure 6.12 The S_N2 reaction is concerted and stereospecific. An S_N2 reaction of a chiral substrate will produce a product with the opposite stereochemical configuration.

Another way to understand the backside trajectory of attack in S_N2 reactions is to inspect the molecular orbitals (MOs) involved. The relevant MOs will be the HOMO of the nucleophile (hydroxide) and the LUMO of the electrophile (methyl bromide), as illustrated below. It should be evident that the best overlap of MOs will occur along the axis of the C–Br bond. Since approach from the direction of the bromine atom cannot lead to a new C–O bond, the remaining possibility is overlap with the red lobe of the LUMO on the left, which is exactly opposite the C–Br bond. Thus, the molecular orbital description of the S_N2 reaction is consistent with the empirical observation of backside attack and inversion of configuration at the reacting center.

(Reproduced, with permission, from Carey FA, Giuliano RM. Organic Chemistry. 9th ed. New York: McGraw-Hill Education; 2014.)

Another important characteristic of S_N2 reactions is sensitivity to the steric environment surrounding both the nucleophile and electrophile. This is a consequence of the need for the nucleophile to have unhindered access to the electrophilic carbon atom, opposite the breaking C–X bond. The best way to see this is to compare space-filling models of methyl bromide and the more hindered carbon atoms in ethyl-, isopropyl-, and finally tert-butyl bromide (Figure 6.13). As additional methyl groups are introduced, the electrophilic carbon atom becomes less and less accessible to nucleophiles. It is not surprising then that the order of relative reactivity for these species is CH₃–Br > CH₃CH₂–Br (CH₃)₂CH–Br (CH₃)₃C–Br.

Figure 6.13 Ball-and-stick and space-filling representations of alkyl bromides with increasing steric bulk surrounding the electrophilic carbon atom. Isopropyl and tert-butyl bromide are essentially unreactive in S_N2 reactions. (Reproduced, with permission, from Carey FA, Giuliano RM. Organic Chemistry. 9th ed. New York: McGraw-Hill Education; 2014.)

While primary alkyl halides generally react readily in S_N2 reactions, there are cases where substitution farther out from the reactive center can still preclude reaction. This is illustrated for the alkyl halide electrophiles shown below. While all are primary alkyl halides, increasing steric bulk at the beta-carbon has a dramatic effect on reactivity. This is a consequence of the bulky isopropyl and tert-butyl substituents blocking approach of nucleophiles opposite the electrophilic C–Br bond. An example of an important S_N2 reaction in biology is provided in Box 6.2.

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