Electrophilic aromatic directing groups

{{Short description|none}} In electrophilic aromatic substitution reactions, existing substituent groups on the aromatic ring influence the overall reaction rate or have a directing effect on positional isomer of the products that are formed.

An '''electron donating group''' ('''EDG''') or '''electron releasing group''' ('''ERG''', '''Z''' in structural formulas) is an atom or functional group that donates some of its electron density into a conjugated π system via resonance (mesomerism) or inductive effects (or induction)—called '''+M''' or '''+I''' effects, respectively—thus making the π system more nucleophilic.<ref name="UCLA EWG">{{cite web|title=Electron withdrawing group|url=http://www.chem.ucla.edu/harding/IGOC/E/electron_withdrawing_group.html|work=Illustrated Glossary of Organic Chemistry|publisher=UCLA Department of Chemistry|access-date=16 November 2012}}</ref><ref name="substituents">{{cite web|last=Hunt|first=Ian|title=Substituent Effects|url=http://www.chem.ucalgary.ca/courses/350/Carey5th/Ch12/ch12-8b.html|publisher=University of Calgary Department of Chemistry|access-date=16 November 2012}}</ref> As a result of these electronic effects, an aromatic ring to which such a group is attached is more likely to participate in electrophilic substitution reaction. EDGs are therefore often known as '''activating groups''', though steric effects can interfere with the reaction.

An '''electron withdrawing group''' (EWG) will have the opposite effect on the nucleophilicity of the ring. The EWG removes electron density from a π system, making it less reactive in this type of reaction,<ref name="substituents" /><ref name="UCLA EDG">{{cite web|title=Electron donating group|url=http://www.chem.ucla.edu/harding/IGOC/E/electron_donating_group.html|work=Illustrated Glossary of Organic Chemistry|publisher=UCLA Department of Chemistry|access-date=16 November 2012}}</ref> and therefore called '''deactivating groups'''.

EDGs and EWGs also determine the positions (relative to themselves) on the aromatic ring where substitution reactions are most likely to take place. Electron donating groups are generally ortho/para directors for electrophilic aromatic substitutions, while electron withdrawing groups (except the halogens) are generally meta directors. The selectivities observed with EDGs and EWGs were first described in 1892 and have been known as the Crum Brown–Gibson rule.<ref>{{cite journal |last1=Brown |first1=A. Crum |author1-link=Alexander Crum Brown |last2=Gibson |first2=John |year=1892 |title=XXX.—A rule for determining whether a given benzene mono-derivative shall give a ''meta''-di-derivative or a mixture of ''ortho''- and ''para''-di-derivatives |url=https://zenodo.org/record/1429690 |journal=J. Chem. Soc. |volume=61 |pages=367–369 |doi=10.1039/ct8926100367}}</ref>

==Categories== thumb|Diagram showing the ''ortho, meta'' and ''para'' positions relative to a substituent X on a benzene ring Electron donating groups are typically divided into three levels of activating ability (The "extreme" category can be seen as "strong".) Electron withdrawing groups are assigned to similar groupings. Activating substituents favour electrophilic substitution about the ''ortho'' and ''para'' positions. <!--This is illustrated by drawing the resonance structures of aniline: [http://s60.photobucket.com/albums/h6/adamboygenius/?action=view¤t=scan0001.jpg]--> Weakly deactivating groups direct electrophiles to attack the benzene molecule at the ''ortho-'' and ''para-'' positions, while strongly and moderately deactivating groups direct attacks to the ''meta-'' position.<ref>{{cite web|url=http://www.mhhe.com/physsci/chemistry/carey/student/olc/graphics/carey04oc/ref/ch12substituenteffects.html |title=Substituent Effects |website=www.mhhe.com|access-date=2 April 2015}}</ref> This is not a case of favoring the meta- position like para- and ortho- directing functional groups, but rather disfavouring the ''ortho''- and ''para''-positions more than they disfavour the ''meta''- position.

=== Activating groups === The activating groups are mostly resonance donors (+M). Although many of these groups are also inductively withdrawing (–I), which is a deactivating effect, the resonance (or mesomeric) effect is almost always stronger, with the exception of Cl, Br, and I.

{| class="wikitable" !Magnitude of activation !Substituent Name (in approximate order of activating strength) !Structure !Type of electronic effect !Directing effect |- |Extreme |oxido group | -O⁻ | +I, +M, metal-hydrogen exchange | rowspan=10 | ''ortho'', ''para'' |- | rowspan="2" |Strong |(substituted) amino groups | -NH₂, -NHR, -NR₂ | rowspan="4" |–I, +M |- |hydroxy and alkoxy groups | -OH, -OR |- | rowspan="3" |Moderate |acylamido groups | -NHCOR |- |acyloxy groups | -OCOR |- |(di)alkylphosphino, alkylthio, and sulfhydryl groups<ref>{{Cite web|url=https://www.masterorganicchemistry.com/2018/01/29/ortho-para-and-meta-directors-in-electrophilic-aromatic-substitution/|title=Ortho-, Para- and Meta- Directors in Electrophilic Aromatic Substitution|last=James|first=Ashenhurst|date=29 Jan 2018|website=Master Organic Chemistry}}</ref> | -PR₂, -SR,

-SH | +M (weak) |- | rowspan="4" |Weak |phenyl (or aryl) group | -C₆H₅ | rowspan="3" | –I, +M;<ref>{{cite book |title= Principles of Organic Synthesis |edition= 3rd |first1= Richard O. C. |last1= Norman |first2= James M. |last2= Coxon |publisher= CRC Press |year= 1993 |isbn= 9780748761623 |pages= 353–354 }}</ref><ref>{{Cite journal|last=Salvatella|first=Luis|date=October 2017|title=The alkyl group is a –I + R substituent|url=http://revistas.unam.mx/index.php/req/article/view/64037|journal=Educación Química|language=en|volume=28|issue=4|pages=232–237|doi=10.1016/j.eq.2017.06.004|hdl=10261/184773|s2cid=46641895 |hdl-access=free}}</ref> though other interactions may be involved as well<ref>{{Cite book |title=Nitration and aromatic reactivity |first1=J. G. |last1=Hoggett |first2=R. B. |last2=Moodie |first3=J. R. |last3=Penton |first4=K. |last4=Schofield |publisher=Cambridge University Press |year=1971 |isbn=0521080290 |location=London |page=[https://archive.org/details/nitrationaromati0000unse/page/200 200] |oclc=205846 |url-access=registration |url=https://archive.org/details/nitrationaromati0000unse/page/200 }}</ref> |- |vinyl group | -CH=CH₂ |- |alkyl groups (e.g. -CH₃, -C₂H₅) | -R |- |carboxylate group<ref name=":2">{{Cite web|url=http://www.ch.ic.ac.uk/local/organic/tutorial/EHS_2.pdf|title=LECTURE 2|last=Smith|first=Ed|date=12 February 2018|website=Handouts for Organic Chemistry Lectures given at Imperial College London, Chemistry|page=3}}</ref> | -CO₂⁻ | +I |} In general, the resonance effect of elements in the third period and beyond is relatively weak. This is mainly because of the relatively poor orbital overlap of the substituent's 3p (or higher) orbital with the 2p orbital of the carbon.

Due to a stronger resonance effect and inductive effect than the heavier halogens, fluorine is anomalous. The partial rate factor of electrophilic aromatic substitution on fluorobenzene is often larger than one at the ''para'' position, making it an activating group.<ref>{{Cite journal|last1=Rosenthal|first1=Joel|last2=Schuster|first2=David I.|date=2003-06-01|title=The Anomalous Reactivity of Fluorobenzene in Electrophilic Aromatic Substitution and Related Phenomena|journal=Journal of Chemical Education|volume=80|issue=6|pages=679–690|doi=10.1021/ed080p679|bibcode=2003JChEd..80..679R|issn=0021-9584}}</ref> Conversely, it is moderately deactivated at the ''ortho'' and ''meta'' positions, due to the proximity of these positions to the electronegative fluoro substituent.

===Deactivating groups=== While all deactivating groups are inductively withdrawing (–I), most of them are also withdrawing through resonance (–M) as well. Halogen substituents are an exception: they are resonance donors (+M), they are ''meta'' directing groups.

Halides are ''ortho'', ''para'' directing groups but unlike most ''ortho'', ''para'' directors, halides mildly deactivate the arene. This unusual behavior can be explained by two properties:

# Since the halogens are very electronegative they cause inductive withdrawal (withdrawal of electrons from the carbon atom of benzene). # Since the halogens have non-bonding electrons they can donate electron density through pi bonding (resonance donation).

The inductive and resonance properties compete with each other but the resonance effect dominates for purposes of directing the sites of reactivity. For nitration, for example, fluorine directs strongly to the ''para'' position because the ''ortho'' position is inductively deactivated (86% ''para'', 13% ''ortho'', 0.6% ''meta''). On the other hand, iodine directs to ''ortho'' and ''para'' positions comparably (54% ''para'' and 45% ''ortho'', 1.3% ''meta'').<ref name=":0">{{Cite book|title=Organic chemistry|last=Jonathan.|first=Clayden|date=2012|publisher=Oxford University Press|others=Greeves, Nick., Warren, Stuart G.|isbn=9780199270293|edition=2nd|location=Oxford|oclc=761379371}}</ref> {| class="wikitable" !Magnitude of deactivation !Substituent Name (in approximate order of deactivating strength) !Structure !Type of electronic effect !Directing effect |- | rowspan="6" |Strong |trifluoromethylsulfonyl group<ref>{{Cite journal|title=Synthesis and Properties of Ring-Deactivated Deuterated (Hydroxymethyl)pyrroles|last1=Andrew|first1=D. Abell|last2=Brent|first2=K. Nabbs|date=12 February 1998|last3=Alan|first3=R. Battersby|journal=Journal of the American Chemical Society |volume=120 |issue=8 |doi=10.1021/ja973656+}}</ref> | -SO₂CF₃ |–I, –M | rowspan="10" |''meta'' |- |(substituted) ammonium groups<ref name=":1">{{Cite book |last=C. |first=Vollhardt, K. Peter |title=Organic chemistry : structure and function |date=2018-01-29 |others=Schore, Neil Eric, 1948- |isbn=9781319079451 |edition=8e |location=New York |oclc=1007924903}}</ref> |<nowiki>-NR</nowiki>₃⁺ (R = alkyl or H) |–I |- |nitro group |<nowiki>-NO</nowiki>₂ | rowspan="3" |–I, –M |- |sulfonic acids and sulfonyl groups |<nowiki>-SO</nowiki>₃H, <nowiki>-SO</nowiki>₂R |- |cyano group |<nowiki>-C≡N</nowiki> |- |trihalomethyl groups (strongest for -CF₃ group) | -CX₃ (X = F, Cl, Br, I) |–I |- | rowspan="4" |Moderate |haloformyl groups | -COX (X = Cl, Br, I) | rowspan="4" |–I, –M |- |formyl and acyl groups | -CHO, -COR |- |carboxyl and alkoxycarbonyl groups | -CO₂H, -CO₂R |- |(substituted) aminocarbonyl groups |<nowiki>-CONH</nowiki>₂, -CONHR,

-CONR₂ |- | rowspan="3" |Weak |fluoro group (''ortho'', ''meta'' positions) | -F | –I, +M (''ortho'') | rowspan="3" |''ortho'', ''para'' |- |nitroso group | -N=O |–I, +M (dimer) or –M (monomer) |- |halo groups | -F(para), -Cl, -Br, -I<ref>{{Cite web|date=2013-10-02|title=Substitution Reactions of Benzene Derivatives|url=https://chem.libretexts.org/Bookshelves/Organic_Chemistry/Supplemental_Modules_(Organic_Chemistry)/Arenes/Reactivity_of_Arenes/Substitution_Reactions_of_Benzene_Derivatives|access-date=2021-09-18|website=Chemistry LibreTexts|language=en}}</ref> |–I, +M (weak) |}

== Traditional rationalizations == Although the full electronic structure of an arene can only be computed using quantum mechanics, the directing effects of different substituents can often be guessed through analysis of resonance diagrams. frameless|300x300px|alt=|border|leftSpecifically, any formal negative or positive charges in minor resonance contributors (ones in accord with the natural polarization but not necessarily obeying the octet rule) reflect locations having a larger or smaller density of charge in the molecular orbital for a bond most likely to break. A carbon atom with a larger coefficient will be preferentially attacked, due to more favorable orbital overlap with the electrophile.<ref>{{Cite book |last=E. |first=Lewis, David |title=Advanced organic chemistry |year=2016 |isbn=9780199758975 |location=New York |oclc=933277973}}</ref> The perturbation of a conjugating electron-withdrawing or electron-donating group causes the π electron distribution on a benzene ring to resemble (''very slightly''!) an electron-deficient benzyl cation or electron-excessive benzyl anion, respectively. The latter species admit tractable quantum calculation using Hückel theory: the cation withdraws electron density at the ''ortho'' and ''para'' positions, favoring ''meta'' attack, whereas the anion releases electron density into the same positions, activating them for attack.<ref>{{Cite book |author=Fleming, Ian |title=Frontier orbitals and organic chemical reactions |date=1976 |publisher=Wiley |isbn=0471018201 |location=London |oclc=2048204}}</ref> This is precisely the result that the drawing of resonance structures would predict.

For example, aniline has resonance structures with negative charges around the ring system:[[File:Anilin delocalization.svg|The amino group can donate electron density through resonance.|394x394px|center|frameless]]

Attack occurs at ''ortho'' and ''para'' positions, because the (partial) formal negative charges at these positions indicate a local electron excess. On the other hand, the nitrobenzene resonance structures have positive charges around the ring system:

[[Image:Nitrobenzene resonance.svg|390x390px|The nitro group can withdraw electron density through resonance.|center|frameless]]Attack occurs at the ''meta'' position, since the (partial) formal positive charges at the ''ortho'' and ''para'' positions indicate electron deficiency at these positions.

Another common argument, which makes identical predictions, considers the stabilization or destabilization by substituents of the Wheland intermediates resulting from electrophilic attack at the ''ortho''/''para'' or ''meta'' positions. The Hammond postulate then dictates that the relative transition state energies will reflect the differences in the ground state energies of the Wheland intermediates.<ref name=":1" /><ref>{{Cite book |author=Carey, Francis A. |title=Organic chemistry |date=2013-01-07 |others=Giuliano, Robert M., 1954- |isbn=9780073402741 |edition=Ninth |location=New York, NY |oclc=822971422}}</ref>

=== Carbonyls, sulfonic acids and nitro === Because of the full or partial positive charge on the element directly attached to the ring for each of these groups, they all have a moderate to strong electron-withdrawing inductive effect (known as the -I effect). They also exhibit electron-withdrawing resonance effects, (known as the -M effect): none|thumb|395x395px|The -M effect of nitrobenzene

Thus, these groups make the aromatic ring very electron-poor (δ+) relative to benzene and, therefore, they strongly deactivate the ring (i.e. reactions proceed much slower in rings bearing these groups compared to those reactions in benzene.)

=== Anilines, phenols, and ethers (such as anisole) === Due to the electronegativity difference between carbon and oxygen / nitrogen, there will be a slight electron withdrawing effect through inductive effect (known as the –I effect). However, the other effect called resonance add electron density back to the ring (known as the +M effect) and dominate over that of inductive effect. Hence the result is that they are EDGs and ''ortho''/''para'' directors.

Phenol is an ortho/para director, but in a presence of base, the reaction is more rapid. It is due to the higher reactivity of phenolate anion. The negative oxygen was 'forced' to give electron density to the carbons (because it has a negative charge, it has an extra +I effect). Even when cold and with neutral (and relatively weak) electrophiles, the reaction still occurs rapidly. thumb|412x412px|The phenolate has a negatively charged oxygen. That is very unstable that the oxygen has a stronger +M effect (compared to phenol) and an extra +I effect.|alt=

=== Alkyl groups === Alkyl groups are electron donating groups. The carbon on that is sp³ hybridized and less electronegative than those that are sp² hybridized. They have overlap on the carbon–hydrogen bonds (or carbon–carbon bonds in compounds like ''tert''-butylbenzene) with the ring p orbital. Hence they are more reactive than benzene and are ''ortho''/''para'' directors.

=== Carboxylate === Inductively, the negatively charged carboxylate ion moderately repels the electrons in the bond attaching it to the ring. Thus, there is a weak electron-donating +I effect. There is an almost zero -M effect since the electron-withdrawing resonance capacity of the carbonyl group is effectively removed by the delocalisation of the negative charge of the anion on the oxygen. Thus overall the carboxylate group (unlike the carboxyl group) has an activating influence.<ref name=":2" /> thumb|The negative charge is spread through both oxygens.|alt=|none

=== Alkylammonium and trifluoromethyl group === These groups have a strong electron-withdrawing inductive effect (-I) either by virtue of their positive charge or because of the powerfully electronegativity of the halogens. There is no resonance effect because there are no orbitals or electron pairs which can overlap with those of the ring. The inductive effect acts like that for the carboxylate anion but in the opposite direction (i.e. it produces small positive charges on the ''ortho'' and ''para'' positions but not on the ''meta'' position and it destabilises the Wheland intermediate.) Hence these groups are deactivating and ''meta'' directing: none|thumb|They have formal or partial positive charges, which deactivates the ring.

=== Halides' competing effects ===

==== Induction versus resonance ==== Fluorine is something of an anomaly in this circumstance. Above, it is described as a weak electron withdrawing group but this is only partly true. It is correct that fluorine has a -I effect, which results in electrons being withdrawn inductively. However, another effect that plays a role is the +M effect which adds electron density back into the benzene ring (thus having the opposite effect of the -I effect but by a different mechanism). This is called the mesomeric effect (hence +M) and the result for fluorine is that the +M effect approximately cancels out the -I effect. The effect of this for fluorobenzene at the ''para'' position is reactivity that is comparable to (or even higher than) that of benzene. Because inductive effects depends strongly on proximity, the ''meta'' and ''ortho'' positions of fluorobenzene are considerably less reactive than benzene. Thus, electrophilic aromatic substitution on fluorobenzene is strongly ''para'' selective.

This -I and +M effect is true for all halides - there is some electron withdrawing and donating character of each. To understand why the reactivity changes occur, we need to consider the orbital overlaps occurring in each. The valence orbitals of fluorine are the 2p orbitals which is the same for carbon - hence they will be very close in energy and orbital overlap will be favourable. Chlorine has 3p valence orbitals, hence the orbital energies will be further apart and the geometry less favourable, leading to less donation the stabilize the carbocationic intermediate, hence chlorobenzene is less reactive than fluorobenzene. However, bromobenzene and iodobenzene are about the same or a little more reactive than chlorobenzene, because although the resonance donation is even worse, the inductive effect is also weakened due to their lower electronegativities. Thus the overall order of reactivity is U-shaped, with a minimum at chlorobenzene/bromobenzene (relative nitration rates compared to benzene = 1 in parentheses): PhF (0.18) > PhCl (0.064) ~ PhBr (0.060) < PhI (0.12).<ref name=":0" /> But still, all halobenzenes reacts slower than benzene itself.

Notice that iodobenzene is still less reactive than fluorobenzene because polarizability plays a role as well. This can also explain why phosphorus in phosphanes can't donate electron density to carbon through induction (i.e. +I effect) although it is less electronegative than carbon (2.19 vs 2.55, see electronegativity list) and why hydroiodic acid (pKa = -10) being much more acidic than hydrofluoric acid (pKa = 3). (That's 10¹³ times more acidic than hydrofluoric acid)

==== Directing effect ==== Due to the lone pair of electrons, halogen groups are available for donating electrons. Hence they are therefore ''ortho'' / ''para'' directors.

=== Nitroso group ===

==== Induction ==== Due to the electronegativity difference between carbon and nitrogen, the nitroso group has a relatively strong -I effect, but not as strong as the nitro group. (Positively charged nitrogen atoms on alkylammonium cations and on nitro groups have a much stronger -I effect)

==== Resonance ====

The nitroso group has both a +M and -M effect, but the -M effect is more favorable.

Nitrogen has a lone pair of electrons. However, the lone pair of its monomer form is unfavourable to donate through resonance. Only the dimer form is available for +M effect. However, the dimer form is less stable in a solution. Therefore, the nitroso group is less available to donate electrons.

Oppositely, withdrawing electron density is more favourable: (see the picture on the right).thumb|369x369px|The -M effect of the nitroso group|alt=|noneAs a result, the nitroso group is a deactivator. However, it has available to donate electron density to the benzene ring during the Wheland intermediate, making it still being an ''ortho'' / ''para'' director.

== Steric effects == There are 2 ''ortho'' positions, 2 ''meta'' positions and 1 ''para'' position on benzene when a group is attached to it. When a group is an ''ortho / para'' director with ''ortho'' and ''para'' positions reacting with the same partial rate factor, we would expect twice as much ''ortho'' product as ''para'' product due to this statistical effect. However, the partial rate factors at the ''ortho'' and ''para'' positions are not generally equal. In the case of a fluorine substituent, for instance, the ''ortho'' partial rate factor is much smaller than the ''para'', due to a stronger inductive withdrawal effect at the ''ortho'' position. Aside from these effects, there is often also a '''steric effect''', due to increased steric hindrance at the ''ortho'' position but not the ''para'' position, leading to a larger amount of the ''para'' product.

The effect is illustrated for electrophilic aromatic substitutions with alkyl substituents of differing steric demand for electrophilic aromatic nitration.<ref>{{Cite book|chapter-url=http://www.rsc.org/images/07_Some_Organic_Reaction_Pathways_tcm18-29996.pdf|title=Some Organic Reaction Pathways|last=Peter|first=Sykes|year=1979|isbn=0851869998|pages=32|chapter=2}}</ref> {| class="wikitable" !Substrate !toluene [-CH₃] !ethylbenzene [-CH₂CH₃] !cumene [-CH(CH₃)₂] !''tert''-butylbenzene [-C(CH₃)₃] |- !''ortho'' product |58 |45 |30 |16 |- !''meta'' product |5 |6 |8 |11 |- !''para'' product |37 |59 |62 |73 |- !''ortho/para'' ratio |1.57 |0.76 |0.48 |0.22 |} The methyl group in toluene is small and will lead the ''ortho'' product being the major product. On the other hand, the ''t''-butyl group is very bulky (there are 3 methyl groups attached to a single carbon) and will lead the ''para'' product as the major one. Even with toluene, the product is not 2:1 but having a slightly less ''ortho'' product.

== Directing effect on multiple substituents == When two substituents are already present on the ring, the third substituent's new location is relatively predictable. If the existing substituents reinforce or the molecule is highly symmetric, there may be no ambiguity. Otherwise:<ref>{{Cite web|url=http://www.wou.edu/las/physci/ch335/lecture/EAS_substituent_effects&synthesis.pdf|title=12.15. Multiple Multiple Substituent Substituent Effects|page=7}}</ref> # The most-activating substituent usually controls over the less-activating one. frameless|center|upright=1|Substituents add ''ortho'' to the amine in diethyl-(''para''-methyl)aniline and ''ortho'' to the amide in ''para''-cyanobenzamide # In particular, ''ortho''/''para'' directors control over ''meta'' ones. frameless|center|upright=1|Substituents add ''ortho'' to the amine in diethyl-(''meta''-trifluoromethyl)aniline and ''ortho'' to the fluoride in ''para''-fluorobenzaldehyde # When multiple substituents are comparably activating, steric hindrance dominates regioselectivity. frameless|center|upright=0.5|Substituents add ''ortho'' to the methyl group in ''para''-(''tert''-butyl)toluene # In particular, the position between two substituents, each ''meta'' to the other, reacts last. frameless|center|upright=0.75|New substituents add ''para'' to either substituent in ''meta''-chlorotoluene

==See also== *Electrophilic aromatic substitution

==References== {{Reflist}}

Category:Functional groups