- General features
- Differences with aromatic electrophilic substitution
- Effects edit
- Of the number of substituents
- From the outgoing group
- Example
- Final comment
- References
The nucleophilic aromatic substitution (SNAr) is a reaction that occurs in organic chemistry, which involves the displacement of a good leaving group by a nucleophile incoming. 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 exits as 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
The upper image outlines what was said in the previous paragraph. The electron attracting group EWG (Electron Withdrawing Group) activates the aromatic ring for 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.
General features
The aromatic ring can be “charged” or “discharged” of electrons depending on what its substituents are (those that replace the original CH 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 deplete 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 aromatic electrophilic substitution; that is, it can donate its electrons to an electrophilic species, E +. However, it will not donate electrons to a Nu - species, since the negative charges would repel each other.
Now, if the ring is poor in electrons, it does not have how to give them to the E + species (SEAr does not occur); on the other hand, it is available to accept the electrons of the Nu - species (the rSNA 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 from 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. Substitution will always occur at the carbon attached to leaving group X.
The last point is also illustrated in the image: the CX 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 will be 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 NO 2 group appears, 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 2 groups present increases (purple and red rings), the substitution takes place at lower and lower temperatures (100 ° C and 30 ° C, respectively).
Therefore, the NO 2 groups accelerate the rSNA and deprive the ring of electrons, making it more susceptible to attack by OH -.
The relative positions of Cl with respect to NO 2 in 4-nitrochlorobenzene, and how these alter the rate of the reaction, will not be explained here; for example, the reaction rates of 2-nitrochlorobenzene and 3-nitrochlorobenzene are different, with 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 that of its fluorinated counterpart:
Effect of the leaving group in SNAr reactions. Source: Gabriel Bolívar.
The explanation for this cannot lie in another variable than the difference between F and Cl. Fluorine is a terrible leaving group, since the CF bond is more difficult to break than the C-Cl bond. Therefore, the breaking of this bond is not the speed determining step for rSNA, but the addition of Nu - to the aromatic ring.
Since fluorine is more electronegative than chlorine, the carbon atom linked to it has a greater electronic deficiency (C δ + -F δ-). Consequently, the carbon of the CF 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
Electrophilic aromatic 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 since there is 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 is no longer aromatic).
The image just shows the last resonance structure, from which the fluorine ends as F -; but in reality said negative charge gets to delocalize even in the oxygen atoms of the NO 2 group. After the addition step comes the elimination step, the last one, which is when the product is finally formed.
Final comment
The remaining NO 2 group can be reduced to the NH 2 group, and from there it is possible to perform further 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 via an activated complex and not an intermediate.
References
- Morrison, RT and Boyd, R, N. (1987). Organic Chemistry. 5th Edition. Editorial Addison-Wesley Interamericana.
- Carey F. (2008). Organic Chemistry. (Sixth edition). Mc Graw Hill.
- Graham Solomons TW, Craig B. Fryhle. (2011). Organic Chemistry. Amines. (10th edition.). Wiley Plus.
- Wikipedia. (2019). Nucleophilic aromatic substitution. Recovered from: en.wikipedia.org
- James Ashenhurst. (September 06, 2019). Nucleophilic Aromatic Substitution (NAS). Recovered from: masterorganicchemistry.com
- Chemistry LibreTexts. (June 05, 2019). Nucleophilic Aromatic Substitution. Recovered from: chem.libretexts.org