Bowman Chem 345 Lecture Notes by Topic. Electrophilic Aromatic Substitution (EAS):

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1 lectrophilic Aromatic Substitution (AS): Aromatic rings have a tendency to be unreactive due to their inherent stability. However, aromatic rings can react given the right incentives. ne way, they can react is with strong electrophiles. In a typical AS reaction, a hydrogen is replaced by an electrophile. General Scheme: H + The reaction mechanism for AS reactions follows three parts. 1.) Formation of the electrophile. This is dependent on the electrophile. 2.) Reaction of a pi bond from the benzene ring to form the sigma intermediate 3.) Deprotonation of the sigma intermediate to reform the aromatic ring. This step is irreversible. General Mechanism: The placement of the electrophile on the aromatic ring and the rate of the reaction is dependent on the substituents on the aromatic ring. The following list of groups on aromatic rings is a good list to know. Activating Groups Deactivating Groups NR 2 R R H X R R S 3 H CN N 2 NR 3 > > > > > ~ > > > > R=H or sp 3 C ortho/para directors X=Halogen meta directors

2 ortho meta The terms ortho, meta, and para are used to show the relative positions between two groups on a benzene ring. Groups ortho to each other have a 1,2 relationship, meta 1,3, and para 1,4. You can often predict whether a group is going to be an ortho/para or a meta director from resonance structures. The incoming electrophile wants to react with the carbons with the highest electron density. Me Y para ortho meta Me Me Me The sites ortho/para to the Me bare a negative charge, so those sites have the highest electron density. Me is an ortho/para director. N N N N The sites ortho/para to the N 2 bare a positive charge, so those sites have the lowest electron density. N 2 is a meta director. A more acceptable way of explaining the activating/directing effects of various substituents is to look at the energy of the reaction. nergy Diagram The rate determining step is the addition of the electrophile to the benzene ring. By the Hammond postulate, the transition state most closely resembles the structure closest in energy to it. In this case, the sigma intermediate is closest in energy to the transition state, therefore the more stable the carbocation intermediate, the more stable the transition state, and the faster the reaction. This can be used to explain why some groups direct ortho/para and some meta.

3 Alkyl Groups: ortho + meta + major para + major In the case of alkyl groups, the resonance structures of the sigma intermediate have a tertiary carbocation when the electrophile adds ortho or para to the alkyl group. If an electrophile adds meta, then only resonance structures with secondary carbocations can be formed. The presence of an alkyl group adjacent to a carbocation lowers the energy by hyperconjugation (the carbocation feeds on some of the electron density from the bonds attached to adjacent sp 3 C s). This lowers the energy of the intermediates (and the subsequent transition states) leading to ortho and para products but not to the meta products.

4 The energies are a bit exaggerated.

5 lectron Withdrawing Groups: Carbonyls, N 2, Nitriles (meta directors) ortho + meta destabilizing + para + destabilizing You can draw the same intermediates for electron withdrawing groups. In this case, the more substituted carbocations in the ortho and para cases are actually destabilizing structures. lectron withdrawing groups raise the energy of the carbocations by pulling electron density away from them. The meta intermediates do not have any stabilizing interactions, but at least they do not have destabilizing interactions.

6 Strong lectron Donating Groups: R, NR 2 (ortho-para directors) Me major ortho Me + Me Me Me meta Me Me + Me Me para Me Me + Me Me Me major In the case of strong electron donating groups, the resonance structures of the sigma intermediate have an extra resonance structure (that has a complete octet) when the electrophile adds ortho or para to the electron donating transition states leading to ortho and para products. This drastically lowers the barrier to the reaction.

7 Weak lectron Donating Groups: Halogens (ortho-para directors) ortho + meta + para + In the case of weak electron donating groups, the resonance structures of the sigma intermediate still have an extra resonance structure which stabilized addition to the ortho and para positions, but the halogens are weak pi donors. They are also very electronegative which destabilizes all of the structures via the inductive effect. While the electron density donated (through the pi system) is enough to direct to ortho and para positions, the electron density withdrawn through the sigma system (inductive effect) makes the reaction proceed at a slower rate. (The inductive effect applies to nitrogen and oxygen as well. But N and are much stronger pi donors and that makes up for any electron density being pulled away through the sigma system).

8 Predicting the product(s). Typically ortho and para directors give mixtures of ortho and para products. The para product is favored by sterics and the ortho product is favored by statistics (two ortho positions as compared to one para position). In most cases, the para product is the major product. I am okay with you defaulting to para being the major product. If you have more than one directing group, then see if there is overlap between the directing group and that will be the most likely product. If there is not overlap between the two, then focus on the most activating group. The major product will likely be the one from that group. If there is a tie, use sterics to break the tie. + para beats ortho 2 N + 2 N both direct to the same spot Me + Me Me is a stronger activating group than Me + There is a tie, so electrophile goes to the spot directed by both groups but is less sterically hindered.

9 We have been using the + as a generic electrophile. The main groups we are going to be using in AS reactions are,, N 2, and carbonyls. The generic reaction conditions for each of these reactions are as follows: 2 Fe 3 2 Al 3 Can work on aromatic rings that are strongly deactivated (ie: meta director) H 2 S 4 HN 3 N Al 3 1.) P 3, DMF 2.) H 2 H There are limited examples of Friedel-Crafts/Vilsmeier-Haack reactions working on deactivated rings (with a meta director). For the purposes of this course, a Friedel-Crafts reaction or Vilsmaier- Haack reaction will need a strong electron donating group (ie:, N) when a meta director is on the aromatic ring.

10 The actual conditions/reagents in the lab that you use may vary depending on the starting material. These will be the standard conditions that you should use in this course. At the end of these notes, there are a couple of variants that use the same principles, but have been optimized to give better yields. Do not memorize the variants. They are only there to serve as examples of what is possible. Halogen lectrophiles: General Conditions: 2 Fe 3 2 Al 3 Can work on aromatic rings that are strongly deactivated (ie: meta director) omination: Chlorination:

11 Literature examples: 1,2,3,4 2 2 Al 3 Al 3 Me Me NBS MeCN NBS MeCN (63%) (97%) Me Me N NBS TBCA CH 3 C 2 H TBCA CF 3 C 2 H 15 min no reaction after 1 week + N N N TBCA + (73%) (7%) (1%) NH 2 NBS MeCN Me NCS (48%) NH 2 Me + (11%) Me NH 2 Me 2 N N TBCA CF 3 C 2 H 24 h 2 N (80%) Me Zr 4 CH 2 2 NCS Zr 4 CH 2 2 NCS Me NCS Me Me NBS Zr 4 CH 2 2 NBS Me Me NH 2 Zr 4 CH /H NH 2 Me 2 /H Zr 4 CH 2 2 Me AcH AcH H N 2 /H H N AcH 1 Zaczek, N. M.; Tyszkiewicz, R. B. J. Chem. d. 1986, 63, Zysman-Colman,.; et. al. Can. J. Chem. 2009, 87, De Almeida, L. S.; De Mattos, M. C. S.; steves, P. M. Synlett 2013, 24, Zhang, Y.; Shibatomi, K.; Yamamoto, H. Synlett 2005, 18,

12 Nitration:

13 Friedel-Crafts Acylation:

14 Vilsmeier-Haack Reaction: There are a couple of examples in the literature of placing a carbonyl on a deactivated aromatic ring by using the Vilsmeier-Haack conditions 5 or Friedel- Crafts 6 but these examples are exceedingly rare. For the purposes of this course, if a meta director is on the aromatic ring, then a strong electron donating group (ie: amine, amide, alkoxy, hydroxyl) needs to be attached to the ring as well. 5 Kumar, M. S. et. al. Tetrahedron Letters 2014, 55, Venkateswarlu, M. et. al. International Journal of rganic Chemistry 2011, 1, Gu, X-L. et. al. Monatshefte fuer Chemie 2015, 146, Zhang, W-J. et. al. Tetrahedron 2013, 69,

15 Literature xamples of Friedel-Crafts Acylation and Vilsmeier-Haack Reaction: 7 7 Kumar, M. S. et. al. Tetrahedron Letters 2014, 55, Venkateswarlu, M. et. al. International Journal of rganic Chemistry 2011, 1, Gu, X-L. et. al. Monatshefte fuer Chemie 2015, 146, Zhang, W-J. et. al. Tetrahedron 2013, 69, Amagat, M. P. Bull. Soc. Chim. 1927, 41, Ali, M. M. et. al. Synthetic Communications 2002, 32,

16 Al 3 N H 2 H P 3 H Al 3 Al 3 P 3 H 2 DMF P 3 DMF H 2

17 Friedel-Crafts Alkylation 8 The electrophile in these reactions is a carbocation or carbocation like molecule (in cases where a primary or methyl carbocation are used). There are multiple ways of making carbocations. An alkyl halide mixed with a Lewis acid, an alcohol with a strong acid (H 2 S 4 ), or an alkene with a strong acid (H 2 S 4 ) are three of the more common ways of generating the electrophile. Mechanism: excess Al 3 8 Loudon, M.; Parise, J. rganic Chemistry 6 th ed. 2016,

18 excess Al 3 H 2 S 4 excess H

19 H 2 S 4 excess Friedel-Crafts alkylation reactions tend to be messy. Multiple or rearranged products can occur. ne problem with the Friedel-Crafts alkylation is that the group that is added to the ring is an activating group. This means that the product is more reactive than the starting material, as a result it is very difficult to stop after one addition and multiple additions occur. Me + + Al More

20 To counteract this, a large excess of starting material is needed to minimize over alkylation. t Al 3 excess Intramolecular reactions where 5 or six member rings form are also a good way to minimize overalkylation. 9 H S F H The electrophile in these cases are a carbocation (or in the case or primary/methyl groups a carbocation like structure). Carbocations are prone to rearrangements. Al 3 excess racemic 49% 27% 9 ight, S. T. J. rg. Chem. 1990, 55,

21 Due to the instability of primary carbocations, they are unlikely to form and rearrange as the leaving group leaves as depicted above. However, if you show a step wise mechanism like below, I will accept it. In short, be very careful when using Friedel-Crafts alkylation. It is very easy for the wrong product or multiple products to be made in this fashion.