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7.4: Nucleophiles and Electrophiles

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  • The Lewis acid–base model is more inclusive than the Brønsted–Lowry model, but we often use the Brønsted–Lowry model because it is easier to follow the proton transfer from one molecule (the acid) to another (the base). In aqueous solutions, the Brønsted–Lowry theory also allows us to use the concept of pH to quantify acidity (as we will see shortly). Both the Lewis and Brønsted–Lowry models capture the overarching principle that most chemical reactions are initiated by an electrostatic interaction between a positively-charged portion of a molecule to a negatively-charged portion of the same, or another, molecule.133 As we will see in the next chapter, molecules must collide with one another in order for reactions to occur between them— they do not react at a distance. When the reacting particles collide, there has to be some continuous pathway through which bonds rearrange and produce products. The first step in this pathway often involves Coulombic (electrostatic) interactions between specific regions of the molecules involved. Of course, whether or not such Coulombic interactions are stable depends upon the kinetic energies of the colliding molecules and exactly how they collide with one another. Catalysts often speed reactions by controlling how molecules collide with or interact with one another. This figure shows the reaction of H2O and NH3, in which the positive end of one molecule interacts with the negative end of the other. If we consider this as a Lewis acid–base reaction, the same principle holds true. It turns out that we can profitably consider a wide range of reactions using the principle of Coulombic attraction. For example, ammonia (and other nitrogen compounds) can react with carbon-containing molecules if the appropriate conditions are met.


    In the figure (→) the nitrogen is behaving as a Lewis base, donating its lone pair of electrons to the carbon. However, it is a little more difficult to see the analogy with a Lewis acid at the carbon site. What we can see is that there is an electronegative, polarizing group (in this case a bromine atom) bonded to the carbon. The presence of a bromine atom polarizes the C—Br bond, giving the carbon a slight positive charge. This makes the carbon susceptible to attack by the lone pair of the nitrogen. Since carbon does not have an empty orbital to accept the lone pair into, and carbon can never form more than four bonds, something has to give. What gives is the C—Br bond, which breaks, and the bromine carries away the electrons from the bond with it, producing a bromide ion, Br.


    This type of reaction, while is essentially a Lewis acid-base reactions, is usually described using yet another set of terms, probably because these reactions usually belong in the realm of organic chemistry, which was once considered a distinct chemical discipline. For organic chemists, the species with the lone pair (in this case the NH3) is called the nucleophile (literally, “nucleus-loving”) and is attracted to a positive center of charge. The species that accepts the lone pair of electrons, in this case the CH3Br molecule, is called the electrophile (literally, “electron- loving”). The species that is released from its bond with the carbon is called the leaving group. Leaving groups must be relatively electronegative (as in the case of Br) or stable when associated with an extra pair of electrons. So, good leaving groups are weak bases. Conjugate bases of strong acids are excellent leaving groups because they are stable.

    If we analyze the reaction in the figure further, we see the nitrogen nucleophile approaching the carbon electrophile: as the bond forms between the C and N, the bond breaks between the C and the Br. The bond-breaking and bond-making occur simultaneously. Given what we know about water and aqueous solutions, we might even be so brave as to predict that the product (+NH3CH3 Br) will rapidly lose a proton in aqueous solution to produce CH3—NH2 and H3O+. This kind of reaction is often referred to as a methylation (a –CH3 group is a methyl group). The product is an N-methylated derivative of ammonia.

    As we have already seen, nitrogen compounds are common in biological systems. We now see how these compounds can also act as nucleophiles, and how methylation of nitrogen is a fairly common occurrence with a range of effects. For example, methylation and demethylation of the nitrogenous bases in DNA adenine and cytosine is used to influence gene expression and mark newly synthesized DNA strands from older, preexisting DNA strands. At the same time, various methylated sequences (such as CpG) are much less stable than the unmethylated form, and so more likely to to mutate.134 Methylation reactions are quite common in other biological reactions as well. For example, epinephrine (also known as adrenaline, the fight-or-flight hormone) is synthesized in the body by methylation of the related molecule norepinephrine.



    133 Note reactions between molecules are intermolecular reactions; those that involve a single molecule are intramolecular.


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