Organic Chemistry I: Crash Course Part 5

(1) Structure of organic molecules
(a) connectivity and structural isomerism
(b) electron delocalization and drawing/evaluating resonance contributors
(c) conformational analysis (draw/evaluate chair forms and Newman projections)
(d) stereochemical analysis (E/Z alkenes; 1, 2 similar, or 2 dissimilar stereocenters)
(2) Prediction and explanation of Bronsted Acid-Base reactions (use of pKa table)
(3) Reactions of polar C-X sigma bonds (SN and E reactions & mechanisms)
(4) Electrophilic addition reactions of C-C pi bonds (regioselectivity & mechanisms)
(a) addition of H/eN (strong & weak Bronsted acids)
(b) addition of X/eN (halogenation; halogens & other nucleophiles)
(c) oxidation (mCPBA; OsO4; ozonolysis)
(d) reduction (hydrogenation with regular & poison catalyst; dissolving metal redn)
—-
(5) EAS: Electrophilic Aromatic Substitution (regioselectivity & mechanisms)


A benzene ring is considered very stable. Why is this the case? Due to aromaticity the benzene ring is stabilized!
Unlike alkene reactions, which was discussed in part 4, benzene and other aromatics do not usually undergo addition reactions but rather they will undergo substitution reactions. The reactions are catalyzed by a Lewis acid and in many cases will not occur without this catalyst.
EAS reactions are used for the synthesis of important intermediates that can be used as precursors for the production of pharmaceutical , agrochemical and industrial products. So they have a lot of applicability outside of your chemistry course!

Source: Master Organic Chemistry

The basic format of EAS deals with the following components:
1.Benzene or Aromatic Compound
2.Electrophile : positive character seeking electrons
3.Lewis acid: serving as a catalyst for the reaction
4.EAS Product which has a bond formed as a bond is broken.

Based on prior addition reactions you may assume the following would occur if you have a benzene and Cl2:

Source: Master Organic Chemistry

However, this would NOT occur. Despite addition products usually taking a pi bond electron source and adding this is not what occurs in the case of an aromatic compound like benzene. Instead we get the following:

Source: Master Organic Chemistry

Here, as you can see, there is a substitution reaction that takes place which occurs as the C-H bond breaks to form a C-Cl bond while the other CL will attach to the proton resulting in HCL. Cl2 is NOT a nucleophile here and H- is not a leaving group either.

The addition of a Lewis acid or Bronsted Acid can serve as a catalyst which speeds up the rate of the reaction. This is because when the acid combines with the electrophile component the result is a much stronger and efficient electrophile. Thus, the reaction is quicker with the new and improved electrophile.

Source: Master Organic Chemistry

There are 6 main EAS reactions to keep in your mind. They are as follows:

  • Chlorination
  • Bromination
  • Nitration
  • Sulfonation
  • Friedel-Crafts Alkylation
  • Friedel-Crafts Acylation
Source: Master Organic Chemistry
Source: https://www2.chemistry.msu.edu/faculty/reusch/VirtTxtJml/benzrx1.htm

A few notes about some possible Lewis acids or electrophiles you may encounter:
Keep in mind that some reactions not only prefer Lewis acids to become faster, some reactions will not occur if not catalyzed by the Lewis acid.
-Br2 is not a strong enough electrophile to react with benzene at a reasonable rate. So you will often see it as the following: AlBr3 or FeBr3 to accelerate the reaction.
-Nitration is the substitution of H with NO2, using nitric acid (HNO3) as the source of NO2 and sulphuric acid (H2SO4) as the Lewis acid.
– Sulfonation can be performed by adding sulfur trioxide (SO3) in the presence of sulphuric acid (H2SO4) as the Lewis acid. H gets replaced with the SO3H group.
– For the Alkylation, we start with an alkyl halide “R-X” such as CH3CH2Cl and then add a Lewis acid such as AlCl3 or FeCl3. The result is a weak C–Cl bond, and a great LG which allows for the nucleophile to easily attack. With no Lewis acid there is no alkylation.
-For the acylation, we start with an acyl halide. Addition of any Lewis acid results in the formation of C–C and breakage of C–H.

Remember during the carbocation intermediate step to see which way they will be reacting further (similar to E1 and SN1):
1. The cation may bond to a nucleophile to give a substitution or addition product (coordination).
2. The cation may transfer a proton to a base, giving a double bond product (electrophile elimination).
3. The cation may undergo rearrangement to a more stable carbocation, and then react by mode #1 or #2.

Substituted Reactions of Benzene Derivatives
There are a few more factors to consider with EAS:
Activation/Deactivation and Conjugation
1.The activation and deactivation potential of the different groups. This can impact whether the group is electron donating or electron withdrawing.
Below: electron donating substituents (blue dipoles) activate the benzene ring toward electrophilic attack, and electron withdrawing substituents (red dipoles) deactivate the ring (make it less reactive to electrophilic attack).

Source: https://www2.chemistry.msu.edu/faculty/reusch/VirtTxtJml/benzrx1.htm

Why are some activating while others are deactivating? That has to do with a few things:
1. Inductive effects of the substituent because of electronegativity.
2. Conjugation
-If the atom bonded to the ring has one or more non-bonding valence shell electron pairs, as do nitrogen, oxygen and the halogens, electrons may flow into the aromatic ring by p-π conjugation (resonance)
-polar double and triple bonds conjugated with the benzene ring may withdraw electrons
-the charge distribution in the benzene ring is greatest at sites ortho and para to the substituent.
-nitrogen and oxygen activating groups displayed in the top row of the previous diagram, electron donation by resonance dominates the inductive effect and these compounds show exceptional reactivity in electrophilic substitution reactions.
-Although halogen atoms have non-bonding valence electron pairs that participate in p-π conjugation, their strong inductive effect predominates, and compounds such as chlorobenzene are less reactive than benzene.
-Alkyl substituents such as methyl increase the nucleophilicity of aromatic rings in the same fashion as they act on double bonds.

Source: https://www2.chemistry.msu.edu/faculty/reusch/VirtTxtJml/benzrx1.htm

The Site at Which the Substitution Occurs
It is also important to consider at which site the substitution will occur. Since a mono-substituted benzene ring has two equivalent ortho-sites, two equivalent meta-sites and a unique para-site, three possible constitutional or structural isomers may be formed in such a substitution. If reaction occurs equally well at all available sites, the expected statistical mixture of isomeric products would be 40% ortho, 40% meta and 20% para. But, as you can see in the table below this is not an even mixture and differs greatly based on the substituent and the reaction taking place. EAS usually occurs ortho or para to electron donating groups, such as amines, due to the stabilization of the intermediate positive charge.

Source: https://www2.chemistry.msu.edu/faculty/reusch/VirtTxtJml/benzrx1.htm
Source: https://www2.chemistry.msu.edu/faculty/reusch/VirtTxtJml/benzrx1.htm

As you can see here, the different reactions can yield different amounts of each of the products. In some cases they will be predominantly one product whereas in others like chlorination or nitration with -CH3 it is a more even split. These different products are defined as Ortho, Meta or Para.


References:
https://www.masterorganicchemistry.com/2017/07/11/electrophilic-aromatic-substitution-introduction/#two

https://www2.chemistry.msu.edu/faculty/reusch/VirtTxtJml/benzrx1.htm

http://www.chem.ucalgary.ca/courses/350/Carey5th/Ch12/ch12-2.html

Published by Magda Wojtara

Magda Wojtara is Junior at the LSA Honors College at the University of Michigan-Ann Arbor on a pre-med track with a major in Neuroscience. In her free time, she write articles, volunteers at a chronic pain outpatient facility with UM Medicine, does research, competes in HOSA, and, of course, enjoys photography and singing. In her spare time she manages her own travel and lifestyle blog: @journeythedestiantion on instagram and journeythedestination.weebly.com

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