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Meso substituion

 The meso- prefx is used when substituents occupy a benzylic position, when the frst carbon

covalently bonds adjacent to a benzene or other aromatic ring.

Organic chemistry 2! "romaticity # nucleophilic aromatic substitution, benzyne

"pr 2$, 2$%& ' ericmini(el ' )ambridge, M" ' chem#2$

These are my notes from lecture 29 of Harvard's Chemistry 20: Organic Chemistry course,

delivered by r! "yan #$oering on %$ril 20, 20&!

*ucleophilic aromatic substitution

+ast time, we discussed aromatic reactions with electrophiles, which are very common reactions.

 Today we discuss aromatic reactions with nucleophiles, in which the aromatic acts as an

electrophile. These are much rarer.

ith electron#withdrawing groups

" classic example is as -ollows!

n the aryl halide at le-t, the carbons should be named relative to the chloride!

http://www.cureffi.org/tag/chem-20http://www.cureffi.org/2015/04/17/organic-chemistry-28/http://www.cureffi.org/2015/04/17/organic-chemistry-28/http://www.cureffi.org/tag/chem-20

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 The chloride itsel- is the /ipso/ position, so swapping out #)l -or #O)01 is an ipso substitution.

- you thin( through the mechanism o- this, at frst it doesnt ma(e sense!

• t cant be an 3*2 reaction, because i- you imagine the )01O# ion as a nucleophile, it would

have to attac( the ipso carbon, and weve never had an 3*2 reaction with an

sp

2

 hybridized carbon.• t cant be an 3*% reaction, because -or the )l to depart, leaving behind a carbocation,

would involve having a positive -ormal charge at an sp2 hybridized carbon, which again is

not something that happens. Moreover, such an 3*% reaction would be very slow, but the

reaction in 4uestion is actually -ast.

5ut some insight can be gained by noticing that the reaction will not happen without the

*O2 electron#withdrawing groups!

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t turns out that )01O# does indeed attac( at the ipso carbon, but in the intermediate, the )01O

and the )l areboth bound at once!

 The resonance structures in the intermediate provide enough stabilization to ma(e this possible.

n general, having two ortho#, para#directing, electron#withdrawing groups in the reactant is

su6cient to allow this sort o- reaction to occur.

*ow consider this retrosynthesis problem!

 The only solution is to frst start with a halogen in the desired ipso position, as it is an ortho#,

para#director and will allow you to add the *O2 electron#withdrawing groups, a-ter which you can

swap out the )l -or the )*!

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*ote that the larger halogens 5r and dont participate as well in this chemistry. 7 is actually

better than )l as a leaving group -or this sort o- substitution, however we do not (now how to

ma(e 8uorinated benzene, so here our only option was to use a chlorinated one.

ith benzyne

*ow consider this reaction!

"t frst it seems to violate the rule we have just learned, that you need electron#withdrawing

groups to enable nucleophilic aromatic substitution. 5ut we can gain some insight by noticing

that i- we do this with an extra methyl group, we get an almost &$9&$ mix o- meta and ortho

products!

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)onsiderable evidence indicates that this reaction involves *02# attac(ing and stealing a

hydrogen, almost li(e an :% reaction, creating a weird and reactive intermediate

called benzyne. This is then attac(ed a second time by an *02# that binds, resulting in a

carbanion as the second intermediate. 7inally, this gets protonated using a proton -rom an *01,

yielding the product!

0ere are some more crazy reactions involving benzyne as an intermediate!

 This last reaction has the -ollowing mechanism!

;etrosynthesis practice problems

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=roblem %

=roblem!

3olution!

=roblem 2

=roblem!

3olution!

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=roblem 1

=roblem!

3olution!

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