Aromatic nucleophilic substitution effects, examples

1601
David Holt

The aromatic nucleophilic substitution (SNAr) is a reaction that occurs in organic chemistry, which consists of the displacement of a good leaving group by an incoming nucleophile. From the point of view of its mechanism and electronic aspects, it is the opposite side of the electrophilic aromatic substitution (SEAr).

Generally, the leaving group is a halogen, which comes out as a halide anion X-. This reaction can only take place if the aromatic ring (mostly benzene) is deficient in electrons; that is, if it has electron-withdrawing substituent groups.

General equation for an aromatic nucleophilic substitution. Source: Sponk [Public domain]

The upper image outlines what was said in the previous paragraph. The electron attractor group EWG (for its acronym in English: Electron Withdrawing Group), activates the aromatic ring for the nucleophilic attack of the negative species Nu-. It can be seen that an intermediate is formed (in the center), from which the halide X is released or exits-.

Note that in simple terms X is substituted for Nu in an aromatic ring. This reaction is very versatile and necessary in the synthesis of new drugs, as well as in synthetic organic chemistry studies..

Article index

  • 1 General aspects
    • 1.1 Differences with electrophilic aromatic substitution
  • 2 Effects
    • 2.1 Of the number of substituents
    • 2.2 From the leaving group
  • 3 Example
    • 3.1 Final comment
  • 4 References

General features

The aromatic ring can be “charged” or “discharged” of electrons depending on what its substituents are (those that replace the original C-H bond).

When these substituents can donate electron density to the ring, they are said to enrich it with electrons; If, on the contrary, they are attractors of electron density (the EWG mentioned above), then it is said that they impoverish the ring of electrons.

In either case, the ring is activated for a specific aromatic reaction, while it is deactivated for the other..

For example, an electron-rich aromatic ring is said to be active for electrophilic aromatic substitution; that is, it can donate its electrons to an electrophilic species, E+. However, it will not donate electrons to a Nu species-, since negative charges would repel each other.

Now, if the ring is poor in electrons, it has no way to give them to species E+ (SEAr does not occur); on the other hand, it is willing to accept electrons of the Nu species- (the SNAr is developed).

Differences with aromatic electrophilic substitution

Once the general input aspects have been clarified, some differences between the SNAr and the SEAr can now be listed:

- The aromatic ring acts as an electrophile (electron deficient) and is attacked by a nucleophile.

- A leaving group X is substituted on the ring; not an H+

- Carbocations are not formed, but intermediaries with a negative charge that can be delocalized by resonance

- The presence of more attractor groups in the ring accelerates the substitution instead of slowing it down

- Finally, these groups do not have directive effects on where (on which carbon) the substitution will occur. The substitution will always occur on the carbon attached to the leaving group X.

The last point is also illustrated in the image: the C-X bond breaks to form the new C-Nu bond.

Effects edit

Of the number of substituents

Naturally, the more electron-poor the ring, the faster the rSNA and the less drastic the conditions required for it to occur. Consider the following example represented in the image below:

Effects of substituents on 4-nitrochlorobenzene substitutions. Source: Gabriel Bolívar.

Note that 4-nitrochlorobenzene (blue ring) requires drastic conditions (high pressure and a temperature of 350 ºC) for the substitution of Cl by OH to occur. In this case, chlorine is the leaving group (Cl-), and hydroxide the nucleophile (OH-).

When the group NO appearstwo, which is an electron attractor (green ring), the substitution can be carried out at a temperature of 150 ° C at ambient pressure. As the number of NO groups increasestwo present (purple and red rings), the substitution takes place at lower and lower temperatures (100ºC and 30ºC, respectively).

Therefore, the groups are NOTtwo accelerate rSNA and deprive the ring of electrons, making it more susceptible to OH attack-.

The relative positions of Cl with respect to NO will not be explained here.two in 4-nitrochlorobenzene, and how these alter the rate of the reaction; For example, the reaction rates of 2-nitrochlorobenzene and 3-nitrochlorobenzene are different, the latter being the slowest compared to the other isomers.

From the outgoing group

Retaking 4-nitrochlorobenzene, its substitution reaction is slower when compared to its fluorinated counterpart:

Effect of the leaving group in SNAr reactions. Source: Gabriel Bolívar.

The explanation for this cannot lie in any other variable than the difference between F and Cl. Fluorine is a terrible leaving group, since the C-F bond is more difficult to break than the C-Cl bond. Therefore, the breaking of this link is not the determining step of the speed for the SNAr, but the addition of the Nu- to the aromatic ring.

Since fluorine is more electronegative than chlorine, the carbon atom linked to it has a greater electronic deficiency (Cδ+-Fδ-). Consequently, the carbon of the C-F bond is much more susceptible to being attacked by Nu- than that of the C-Cl bond. That is why the substitution of F for OH is much faster than that of Cl for OH.

Example

Aromatic electrophilic substitution of 2-methyl-4-nitrofluorobenzene with para-cresol. Source: Gabriel Bolívar.

Finally, an example of this type of organic reactions is shown below in the image above. Para-cresol does not appear to be a nucleophile; but having a basic medium, its OH group is deprotonated, remaining as a phenoxide anion, which does attack 2-methyl-4-nitrofluorobenzene.

When this attack occurs, the nucleophile is said to add to the electrophile (the aromatic ring of 2-methyl-4-nitrofluorobenzene). This step can be seen on the right of the image, where the intermediate compound is formed with both substituents belonging to the ring.

When para-cresol is added, a negative charge appears that is delocalized by resonance within the ring (note that it stops being aromatic).

The image barely shows the last resonance structure, from which the fluorine ends as F-; but in reality said negative charge gets delocalized even in the oxygen atoms of the NO grouptwo. After the addition step comes the elimination step, the last one, which is when the product is finally formed.

Final comment

Group NOtwo remnant can be reduced to the NH grouptwo, and from there it is possible to carry out more synthesis reactions to modify the final molecule. This highlights the synthetic potential of rSNA, and that its mechanism also consists of two steps: one for addition and the other for elimination..

Currently, however, there is experimental and computational evidence that the reaction actually proceeds according to a concerted mechanism, where both steps occur simultaneously through an activated complex and not an intermediate..

References

  1. Morrison, R. T. and Boyd, R, N. (1987). Organic chemistry. 5th Edition. Editorial Addison-Wesley Interamericana.
  2. Carey F. (2008). Organic chemistry. (Sixth edition). Mc Graw Hill.
  3. Graham Solomons T.W., Craig B. Fryhle. (2011). Organic chemistry. Amines. (10th edition.). Wiley plus.
  4. Wikipedia. (2019). Nucleophilic aromatic substitution. Recovered from: en.wikipedia.org
  5. James Ashenhurst. (September 06, 2019). Nucleophilic Aromatic Substitution (NAS). Recovered from: masterorganicchemistry.com
  6. Chemistry LibreTexts. (June 05, 2019). Nucleophilic Aromatic Substitution. Recovered from: chem.libretexts.org

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