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Benzene first reacts with the reagents $\ce{CH3Cl/AlCl3}$, to attach a methyl ($\ce{CH3}$) group to the benzene ring.

Then I suggested reacting with $\ce{OH-}$. Because the methyl group is an activator, it will cause the $\ce{OH-}$ electrophile to attack either in the para or ortho positions. In this case I suggest it will attack the ortho position. Now we have two activators, hydroxyl and methyl, but because hydroxyl is a stronger activator, the position where the next molecule attacks will be controlled by the hydroxyl group.

The next electrophile that attacks is the $\ce{NO2+}$, through the reaction $\ce{HNO3/H2SO4}$, the nitro group will attack the para position of the benzene and we get our final product 2-methyl-4-nitrophenol.

However, I am not 100% sure if the methyl group should be introduced first to form toluene or the hydroxyl group to form a phenol.

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    $\begingroup$ OH- is nucleophile not electrophile. $\endgroup$ – Mithoron Nov 30 '15 at 23:53
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    $\begingroup$ First convert benzene to phenol. Then do nitration since -OH is an Ortho para director. This brings -NO2 to para position. Then use FC alkylation and the only spot available is the Ortho position. $\endgroup$ – Aditya Dev Dec 1 '15 at 3:25
  • $\begingroup$ I agree with Aditya Dev. Also, for future reference, when you have a activating group that directs incoming groups to the ortho and para positions the para position is favored due to steric approach control. $\endgroup$ – Joel J. Dec 1 '15 at 6:02
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There is a lot of good thinking in your proposed synthetic strategy. The one major shortcoming is, as @Mithoron points out, $\ce{OH^{-}}$ is not an electrophile.

We need to introduce a methyl, hydroxy and nitro group onto a benzene ring. If we look into our synthetic "toolbox" here are some thoughts that might come to mind:

  • A methyl group can be readily introduced using the Friedel-Crafts alkylation reaction with$\ce{CH3Cl}$. However, be aware that there are some general issues with the Friedel-Crafts alkylation reaction. For example, if the alkylating agent can rearrange to a more stable carbocation it will likely do so ($\ce{CH3Cl}$ can't rearrange). Also, the mono-alkylated product is more reactive than the starting material, so polyalkylation can occur (but in your case, we can use an excess of benzene - it's cheap - and get a good yield of the desired product toluene). Finally, the Friedel-Crafts alkylation does not work well with deactivated aromatic rings. Therefore, the comment suggesting we run the alkylation after introducing the nitro group is incorrect; we must use the Friedel-Crafts alkylation before we introduce the nitro group.
  • There aren't any easy ways to electrophilically introduce a hydroxy group into an aromatic ring. When I need an aromatic hydroxyl substituent, I think of the Sandmeyer reaction.
  • The nitro group can be introduced via straightforward electrophilic nitration.

There are a lot of ways to pull this synthesis together, but here is a relatively direct proposal.

enter image description here

  • The first step is our Friedel-Crafts alkylation to prepare toluene.
  • Next, we'll introduce our ortho hydroxy substituent. To do this let's first sulfonate using fuming sulfuric acid (oleum) and block the para position. Blocking the para position will simplify our next step - we won't have to separate ortho and para isomers and we will get a higher yield of only the desired ortho (to the methyl group) product. Now the sulfonic acid group (meta-director) and the methyl group reinforce one another and will direct our next electrophile to the position ortho to the methyl group.
  • Now we nitrate using nitric and sulfuric acid and get only the product where the nitro group is ortho to the methyl group.
  • Next, we heat the reaction. The sulfonation reaction is readily reversible, by heating our reaction we can readily remove the sulfonic acid substituent since it has served it's purpose and is no longer needed.
  • Now it's time for the Sandmeyer reaction. We first reduce the nitro group with tin and hydrochloric acid to an amino group. Then we diazotize it and decompose the diazonium salt in the presence of acidic water to introduce our hydroxyl group.
  • Finally we nitrate one more time to introduce the nitro group. The directing effect of the hydroxyl group is much stronger than that of the methyl group and will primarily direct the nitro group into the position para to the hydroxyl.
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  • $\begingroup$ mhhe.com/physsci/chemistry/carey/student/olc/… . I'd go for benzene-benzenesulfonic acid - phenol - ortho-formylation product - kishner-wolf reduction - nitration (mono-nitration is reasonably easy to achieve on cold with weak reagent and orto- and para- produducts should be separatable by water vapor distillation) $\endgroup$ – permeakra Jun 17 '16 at 16:33
  • $\begingroup$ Are we in danger of over alkylating? $\endgroup$ – Leeser Jun 17 '16 at 20:51

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