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Organic Chemistry II

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Nucleophilic Substitution

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Nucleophilic substitution is one of the most fundamental reactions used in organic synthesis.

A "nucleophile" is an electron-rich species. In a nucleophilic substitution, a nucleophile reacts with an alkyl halide to form a product with a new functional group. This reaction is the starting point for a vast array of organic syntheses.

This video will illustrate the principles of two categories of nucleophilic substitutions, demonstrate the effects of different reactants on reaction rate for each, and discuss some applications.

Nucleophilic substitution requires two reactants: a functionalized alkane and a nucleophile.

The functionalized alkane can be an alcohol or a sulfonic halide, but is usually an alkyl halide. In an alkyl halide, the carbon bonded to the halogen is called the "alpha" carbon, and must be sp3-hybridized to undergo nucleophilic substitution. Any carbon bonded to the alpha is a "beta" carbon. Importantly, the halogen is a powerful electron-withdrawing group that causes the alpha carbon to be electron-poor. The alpha carbon is therefore an "electrophile," which means it has a shortage of electrons and can accept more.

A "nucleophile" is the opposite; a species that can donate electrons. It is usually a negatively-charged functional group, such as a chloride ion, or the anion of an organic salt, such as an acetate ion. Nucleophiles generally contain unshared electron pairs.

In a nucleophilic substitution, the nucleophile reacts with the alkyl halide by attacking the electrophilic alpha carbon. The nucleophile acts as a Lewis base, donating an electron pair to the alpha carbon. Meanwhile, the bond between the alpha carbon and the halogen breaks. The electrons originally in that bond join with the halogen to form a halide leaving group.

A nucleophilic substitution can occur through one of two mechanisms. The first begins with a slow nucleophilic attack on the backside of the alpha carbon-the side opposite the halogen-followed by the fast departure of the leaving group. Since both the alkyl halide and the nucleophile take part in the slow step, this mechanism is called "Substitution: Nucleophilic Bimolecular," or "SN2," for short. The SN2 mechanism concludes with the other bonds on the alpha carbon changing their orientations and inverting the configuration. Since the nucleophile only attacks the backside of the alpha carbon, the mechanism yields only one, inverted stereoisomer of the product.

The other mechanism begins with the slow dissociation of the alkyl halide into a leaving group and a "carbocation," a highly-reactive, positively-charged carbon. Unlike in the SN2 mechanism, the nucleophile can attack from either side. Both stereoisomers are produced, a distinction experimentally detected by measuring optical rotation. Since only one molecule-the alkyl halide-takes part in the slow step, this mechanism is called "Substitution, Nucleophilic Unimolecular," or "SN1."

Now that we've seen the mechanisms of nucleophilic substitution, let's explore how it applies to different reactants under different conditions.

In this section, we will examine the effects of alkyl halide structure, leaving group selection, and solvent polarity on the SN1 mechanism. The conditions have been chosen to suppress SN2 reactions.

First, we study the effect of alkyl halide structure. Measure 2 mL of 0.1 M silver nitrate in absolute ethanol into three test tubes.

Add 2 drops of 1-bromobutane to the first test tube, 2 drops of 2-bromobutane to the second test tube, and two drops of 2-bromo-2-methylpropane into the third test tube. Record the time at which the reaction starts.

Apply a stopper to each tube and shake.

Record the time at which the solution becomes turbid or a precipitate appears, indicating the formation of insoluble silver bromide.

Next, we turn to the effects of different leaving groups. Measure 2 mL of 0.1 M silver nitrate in absolute ethanol into two test tubes.

Add 2 drops of 2-bromo-2-methylpropane into the first test tube, and 2 drops of 2-chloro-2-methylpropane into the second. As before, record the time at which the reaction starts, apply a stopper to each tube, shake, and record the time at which a precipitate appears.

Finally, to study the effect of different solvents, measure 2 mL of 0.1 M silver nitrate in absolute ethanol into a test tube. Measure 2 mL of 0.1 M silver nitrate in 95% acetone into a second test tube. Add 2 drops of 2-bromo-2-methylpropane into each test tube.

Again, record the time at which the reaction starts, stopper and shake each tube, and record the time at which a precipitate appears.

The rate of an SN1 reaction heavily depends on the nature of the alkyl halide and the solvent.

First, let's examine the structure of the alkyl halide. In this demonstration, 2-bromo-2-methylpropane reacted at a much faster rate than 2-bromobutane, which in turn reacted faster than 1-bromobutane.

These results stem from the nature of the carbocation intermediate formed in the slow initial step of the SN1 mechanism. Carbocations stabilize themselves by dispersing the alpha carbon's positive charge over the beta carbons through polarization and hyperconjugation. This stabilizing effect is greatest in tertiary alkyl halides, which have several beta carbons, and which therefore form carbocations at the fastest rate during an SN1 reaction. Secondary and primary alkyl halides have progressively smaller stabilization effects, and thus progressively lower reaction rates.

Now let's explore the leaving group. In this demonstration, 2-bromo-2-methylpropane reacted at a faster rate than 2-chloro-2-methylpropane.

This is because bromine forms a weaker bond with the alpha carbon compared to chlorine. More generally, halogens found lower on the periodic table form weaker bonds than those found higher on the table. The rate of the initial dissociation step in an SN1 mechanism increases with decreasing bond strength. This trend is common to both the SN1 and SN2 mechanisms.

We now turn to solvent effects. In this demonstration, the reaction between 2-bromo-2-methylpropane and silver nitrate occurred at a faster rate when dissolved in ethanol than in acetone.

Ethanol is highly polar and protic: it has an electropositive terminal hydrogen atom and is therefore capable of forming hydrogen bonds. It is therefore more effective at stabilizing both the carbocation and the leaving group than acetone, which is less polar and aprotic. Generally, the rates of SN1 reactions increase with the polarity of the solvent.

We now explore the effects of alkyl halide structure, leaving group, and solvent polarity on the SN2 mechanism. Again, conditions have been chosen to suppress SN1 reactions.

We begin by studying the effect of alkyl structure around the alpha carbon. Measure 2 mL of 15% sodium iodide in acetone into three test tubes. Add 2 drops of 1-bromobutane to the first test tube, 2 drops of 2-bromobutane into the second, and 2 drops of 2-bromo-2-methylpropane into the third. Record the time required for the precipitate, sodium bromide, to form as before.

Next, we examine the effect of alkyl structure around the beta carbon. Measure 1 mL of 15% sodium iodide in acetone into two test tubes. Add 2 drops of 1-bromobutane to the first test tube, and 2 drops of neopentyl bromide to the second. Record the time of reaction as before.

Finally, we turn to solvent polarity effects. Add 1 mL of 15% sodium iodide in ethanol into the first test tube, and 1 mL 15% sodium iodide in acetone to the second. Add 2 drops of 1-bromobutane to both, and record the time required for a precipitate to form.

First, let's examine the alkyl structure around the alpha carbon. In this example, 1-bromobutane reacted at the fastest rate, 2-bromobutane reacted more slowly, and 2-bromo-2-methylpropane slowest of all. These results are opposite those found in SN1 reactions.

The difference is due to geometry. Increasing the number of beta carbons reduces the exposed area on the alpha carbon over which a successful backside nucleophilic attack can occur. This phenomenon is called "steric hindrance." Primary alkyl halides are the least sterically hindered, and experience the fastest rates of SN2 reaction, while tertiary alkyl halides are most hindered, and experience the slowest reactions.

Next, we turn to the alkyl structure around the beta carbons. 1-Bromobutane reacted instantaneously while neopentyl bromide didn't react at all.

This is also explained through steric hindrance. The presence of bulky groups on the beta carbon again reduces the area on the alpha carbon exposed to nucleophilic attack. A sterically hindered beta carbon experiences a lower reaction rate than an unhindered one.

Finally, we look at solvent effects. The rate of reaction of 1-bromobutane in acetone is much greater than it is in ethanol. This is contrary to the results of the SN1 reaction.

This is because in SN2 reactions, polar protic solvents like ethanol stabilize the nucleophile, making it less reactive and therefore decreasing the rate of reaction. By contrast, aprotic solvents like acetone cannot stabilize the nucleophile to the same extent.

To summarize: the rates of SN2 reactions decrease through steric hindrance on both alpha and beta carbons. This is contrary to SN1 reactions, where beta carbons stabilize the carbocation and increase the rate. The rates of both reactions increase as the bond strength between the leaving group and the alpha carbon decreases. Finally, polar protic solvents retard SN2 reactions by stabilizing the nucleophile, but accelerate SN1 reactions by stabilizing intermediates. With these results in mind, let's examine some applications.

Nucleophilic substitution is a key step in peptoid polymerization. Peptoids, synthetic monomers related to peptides, provide a straightforward approach to the design of highly-tuned synthetic proteins. The polymers are formed by alternately brominating secondary amines and replacing the resulting terminal bromide with an amine through nucleophilic substitution. This method can be used to produce polymeric chains and self-assembled nanosheets.

Another application is in the fabrication of cell culture substrates. Highly automated lithography techniques have been developed to create patterns with 10-micron features on gold coated substrates. A polymer is then printed into the features and reacted through nucleophilic substitution to add azides or other ligands to its surface. This provides a highly controlled surface over which cells can be cultured, and permits exploration of the impact of the ligands on cell growth and behavior.

You've just watched JoVE's introduction to nucleophilic substitution. You should now understand the SN1 and SN2 mechanisms, the effects of different alkyl halides and solvents on each, and some applications. Thanks for watching!

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