Disubstituted Benzenes: The Strongest Electron-Donor “Wins”

Having gone through the mechanism of electrophilic aromatic substitution, explored activating and deactivating substituents, and seen the importance of directing groups, let’s now take the opportunity to use these concepts to answer some slightly thornier questions.

Table of Contents

1. Electrophilic Aromatic Substitution With Two Directing Groups: Which Group “Wins” ?
2. An Easy One: p-Nitroanisole
3. When Two Or More Substituents Are Present, The Directing Group Will Be The Most Activating Substituent.
4. If Attack At Two Or More Positions Is Possible, Pick The Least Sterically Hindered One
5. Nothing Says “Steric Effects” Quite Like A t-Butyl Group
6. Summary: Electrophilic Aromatic Substitution on Disubstituted Benzenes
7. Notes
8. Quiz Yourself!
9. (Advanced) References and Further Reading

1. Electrophilic Aromatic Substitution With Two Directing Groups: Which Group “Wins” ?

Here’s a thorny question: What happens when we perform an electrophilic aromatic substitution reaction when there are two substituents on benzene?

And say that one of them is an ortho-, para- director and one is a meta- director, and they “direct” electrophiles to different carbons on the ring?

Which directing group “wins?”.

2. An Easy One: p-Nitroanisole

Let’s start with 1-methoxy-4-nitrobenzene, which also goes by the name, p-nitroanisole.  Say we try to perform an electrophilic aromatic substitution reaction. Where does the electrophile react? What’s the directing group, OCH₃ or NO₂ ?

 [Note that I’ve used “chlorination” as an example of an electrophilic aromatic substitution reaction, but the principles we will learn in this post apply to all electrophilic aromatic substitution reactions].

The first thing to do is to analyze each substituent individually.

• The –OCH₃ is an ortho-,para- director, but since the para- position is already substituted (with NO₂), only the ortho- positions are available.
• The –NO₂ is a meta- director, and the positions meta- to the NO₂ happen to also be the positions ortho- to the OCH₃.

As it turns out, both substituents direct to the same position (C–2).  This gives us the product 2-chloro-1-methoxy-4-nitrobenzene, which indeed is the major product. [Note 1]

3. When Two Or More Substituents Are Present, The Directing Group Will Be The Most Activating Substituent.

That example was a little too easy. Let’s look at a slightly more ambiguous example: p-methylanisole. Here there are two o-, p- directors: –OCH₃ and –CH_3. 

The tricky part is that they each direct to different carbons. So which substituent “wins” here?

Here’s a good rule of thumb:

 Rule #1: When two or more substituents are present on an aromatic ring, the directing group will be the most activating substituent.
(that is, the more activating substituent “wins”)

Here is a useful (but not comprehensive) ranking of activating / deactivating groups:

Since OCH₃ is a more activating substituent than CH₃ (i.e. OCH₃ accelerates the rate more, because it is a better electron-donor),  the substituent will end up ortho to the OCH₃, not ortho to CH₃.

A more technical way of describing our rule is: since the rate determining step in electrophilic aromatic substitution is formation of the (electron-poor) carbocation intermediate, the substituent which is most electron-donating will result in the lowest-energy transition state and therefore the lowest activation energy, and therefore will determine the major product.

4. If Attack At Two Or More Positions Is Possible, Pick The Least Sterically Hindered One

Here’s another disubstituted example. m-dimethoxybenzene has two identical groups, both of which are ortho-, para- directors.

When we analyze the influence of the directing groups, we again see that their directing effects are additive.  Attack at three positions is “favored”: C-2 (in between the two methoxy groups), C-4, and C-6.

As it turns out, attack at C-4 / C-6 will result in the same product, so we really have only two reasonable products to consider.

Which of the two products will dominate?

Attack at C-2, C-4, and C-6 is equally favorable from an electronic standpoint (that is, they are all equally electron-rich). However, they are not equally favorable from a steric standpoint.

The C-2 carbon is flanked by two methoxy groups, while the C-4 and C-6 carbons are adjacent only to one. Attack at C-2 will be much slower owing to to this greater steric hindrance.

Here comes the second important rule of thumb:

Rule #2: When attack at two or more electronically equivalent sites is possible, the electrophile will favor the position flanked by the fewest number of substituents. 

You might recall that we observed this effect previously in electrophilic aromatic substitution reactions of mono-substituted benzene derivatives like methoxybenzene. Even though there are two available ortho- positions, the para- is the major product because it’s less sterically hindered!

5. Nothing Says “Steric Effects” Like A t-Butyl Group

Let’s finish with a last example that lets us tie these examples together.  1-t-butyl-3-nitrobenzene.

Here we again have a situation where two groups direct to different positions.

What’s a stronger activating group, t-butyl or nitro? (hint : the answer to a question like this is almost never “nitro”  : – ) ) .  This would suggest that substitution would occur at C-2, C-4, and/or C-6.

Which of these three positions is flanked by the fewest substitutents? Clearly, C-2 is out, being flanked by two groups. This leaves us with C-6 and C-4, which are each flanked by a single group.

However, nothing says “STERIC EFFECTS” quite like a t-butyl group. In this case, C-6 is adjacent to the hugely bulky t-butyl group while attack at C-4 is adjacent to the relatively small NO₂ group. So in this case, we’d expect to obtain only one major product.

6. Summary: Electrophilic Aromatic Substitution on Disubstituted Benzenes

When faced with trying to predict the product of an electrophilic aromatic substitution reaction of a disubstituted benzene, there are two important rules of thumb:

1. The most activating group will act as the directing group.
2. Among positions that are similarly “electronically favored”,  the site with the fewest adjacent substituents is more likely to be the site of attack.

(Or, as a wag might describe it, it all boils down to  “electronics” and “sterics”).  

One can apply these two principles to a large variety of commonly encountered situations.

In the next series of posts, we’ll go through some key electrophilic aromatic substitution reactions in detail. Next up: halogenation.

Notes

Note 1. Note that this “addition” of directing group effects will be observed any time there is an “ortho” or “para” relationship between an ortho,para– director and a meta– director.

Note 2. Although an example with two meta- directors wasn’t included, the same principles apply. One has to look at a table that ranks substituents in detailed order of deactivating ability (esters are less deactivating than nitro groups, for example, and would “win” in a competition experiment). One of the complications here is that when there are too many deactivating groups on the benzene ring, certain electrophilic aromatic substitution reactions stop working altogether since the aromatic ring isn’t nucleophilic enough (Friedel-Crafts reactions are in that category)

Note 3. [Advanced]. Not covered here is the ortho- effect. When a meta-directing group is meta to an ortho-para directing group, the incoming group primarily goes ortho- to the meta- directing group rather than para-.  For example, with 1-chloro-3-nitrobenzene, one might expect that two products are formed in roughly equal amounts (perhaps even a bit more of 1,2-dichloro-4-nitrobenzene, since Cl is less sterically demanding than NO₂ (A values: 0.43 for Cl, 1.1 for NO₂).

In fact the dominant product is 1,4-dichloro-2-nitrobenzene, and almost no 1,2-dichloro-4-nitrobenzene is formed. The reason is not well understood but is likely due to be through intramolecular assistance from the meta-directing group. [See March’s Advanced Organic Chemistry 5th ed. p. 688 and references therein. ]

Quiz Yourself!

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(Advanced) References and Further Reading

1. —The nature of the alternating effect in carbon chains. Part V. A discussion of aromatic substitution with special reference to the respective roles of polar and non-polar dissociation; and a further study of the relative directive efficiencies of oxygen and nitrogen
   Christopher Kelk Ingold and Edith Hilda Ingold
   J. Chem. Soc. 1926, 1310-1328
   DOI: 10.1039/JR9262901310
   An early paper examining the directing effects of 2 substituents on a benzene ring, in this case -OMe and -NHAc.
2. —The nature of the alternating effect in carbon chains. Part VI. A study of the relative directive efficiencies of oxygen and fluorine in aromatic substitution
   Eric Leighton Holmes and Christopher Kelk Ingold
   J. Chem. Soc. 1926, 1328-1333
   DOI: 10.1039/JR9262901328
   This paper discusses the product distribution obtained upon nitration of o-fluoroanisole. The nitration occurs either ortho to the -OMe (66%) or para to -OMe (31%).
3. —The nature of the alternating effect in carbon chains. Part XXIII. Anomalous orientation by halogens, and its bearing on the problem of the ortho–para ratio, in aromatic substitution
   Christopher Kelk Ingold and Charles Cyril Norrey Vass
   J. Chem. Soc. 1928, 417-425
   DOI: 10.1039/JR9280000417
   This paper discusses directing effects in 1,2-dihalobenzenes.
4. Volume effects of alkyl groups in aromatic compounds. Part V. The monosulphonation of p-cymene
   R. J. W. Le Fèvre
   J. Chem. Soc. 1934, 1501-1502
   DOI: 10.1039/JR9340001501
   In p-cymene, the major product obtained upon electrophilic sulfonation is the 2-product (ortho to the methyl group), likely due to sterics.
5. Effects of Alkyl Groups in Electrophilic Additions and Substitutions
   COHN, H., HUGHES, E., JONES, M. and PEELING, M. G.
   Nature 1952, 169, 291
   DOI: 1038/169291a0
   This paper has data comparing the nitration of t-butylbenzene and toluene. T-butylbenzene is much more p-directing than toluene (79.5% para for t-butylbenzene vs. 40% para for toluene), which is likely due to sterics (ortho approach is blocked by the bulkier t-butyl group).
6. Distribution of Isomers in the Mononitration of Ethyl- and Isopropylbenzene. Further Evidence for a Steric Effect in Isomer Distribution
   Herbert C. Brown and W. Hallam Bonner
   Journal of the American Chemical Society 1954, 76 (2), 605-606
   DOI: 10.1021/ja01631a084
   Table II in this paper illustrates that the ortho product obtained from nitration of monoalkylbenzenes decreases as the alkyl group gets larger (e.g. t-butylbenzene yields very little ortho product upon nitration compared to toluene).
7. Some aspects of the nitration of the mononitrotoluenes
   J. G. Tillett
   J. Chem. Soc. 1962, 5142-5148
   DOI: 10.1039/JR9620005142
   In this paper the rates for nitration of all three nitrotoluenes are measured and compared. The major product for nitration of m-nitrotoluene is 3,4-dinitrotoluene, consistent with the strongest donor (ortho-para directing methyl) “winning” over the (meta-directing) nitro group.  Note that nitration of 2,4- or 2,6-nitrotoluene leads to the common explosive 2,4,6-trinitrotoluene (TNT)!