Aromatic compounds orarenes areorganic compounds "with a chemistry typified bybenzene" and "cyclicallyconjugated."[1]The word "aromatic" originates from the past grouping of molecules based on odor, before their general chemical properties were understood. The current definition of aromatic compounds does not have any relation to their odor. Aromatic compounds are now defined as cyclic compounds satisfyingHückel's rule.Aromatic compounds have the following general properties:
Arenes are typically split into two categories - benzoids, that contain a benzene derivative and follow the benzene ring model, and non-benzoids that contain other aromatic cyclic derivatives. Aromatic compounds are commonly used in organic synthesis and are involved in many reaction types, following both additions and removals, as well as saturation and dearomatization.
Heteroarenes are aromatic compounds, where at least onemethine orvinylene (-C= or -CH=CH-) group is replaced by aheteroatom:oxygen,nitrogen (azaarenes), orsulfur.[3] Examples of non-benzene compounds with aromatic properties arefuran, a heterocyclic compound with a five-membered ring that includes a single oxygen atom, andpyridine, a heterocyclic compound with a six-membered ring containing one nitrogen atom. Hydrocarbons without an aromatic ring are calledaliphatic. Approximately half of compounds known in 2000 are described as aromatic to some extent.[4]
![Line bond structure of the heterocycle pyridine[5]](/mt/?noimg=&dark=on&url=https%3a%2f%2fen.wikipedia.org%2fwiki%2fFile%3aPyridin_(vzorec).svg)
![Line bond structure of the heterocycle furan[5]](/mt/?noimg=&dark=on&url=https%3a%2f%2fen.wikipedia.org%2fwiki%2fFile%3aFuran_(vzorec).svg)
![Electron flow through p orbitals for the heterocycle furan[5]](/mt/?noimg=&dark=on&url=https%3a%2f%2fen.wikipedia.org%2fwiki%2fFile%3aOrbital_overlap_of_furan.png)
Aromatic compounds are pervasive in nature and industry. Key industrial aromatic hydrocarbons are benzene,toluene,xylene called BTX. Many biomolecules have phenyl groups including the so-calledaromatic amino acids.
Benzene, C6H6, is the least complex aromatic hydrocarbon, and it was the first one defined as such.[6] Its bonding nature was first recognized independently byJoseph Loschmidt andAugust Kekulé in the 19th century.[6] Each carbon atom in the hexagonal cycle has four electrons to share. One electron forms a sigma bond with the hydrogen atom, and one is used in covalently bonding to each of the two neighboring carbons. This leaves six electrons, shared equally around the ring in delocalized pi molecular orbitals the size of the ring itself.[5] This represents the equivalent nature of the six carbon-carbon bonds all ofbond order 1.5. This equivalency can also explained byresonance forms.[5] The electrons are visualized as floating above and below the ring, with the electromagnetic fields they generate acting to keep the ring flat.[5]
The circle symbol for aromaticity was introduced bySir Robert Robinson and his student James Armit in 1925 and popularized starting in 1959 by the Morrison & Boyd textbook on organic chemistry.[7] The proper use of the symbol is debated: some publications use it toany cyclic π system, while others use it only for those π systems that obeyHückel's rule. Some argue that, in order to stay in line with Robinson's originally intended proposal, the use of the circle symbol should be limited to monocyclic 6 π-electron systems.[8] In this way the circle symbol for a six-center six-electron bond can be compared to the Y symbol for athree-center two-electron bond.[8]
Benzene derivatives have from one to sixsubstituents attached to the central benzene core.[2] Examples of benzene compounds with just one substituent arephenol, which carries ahydroxyl group, andtoluene with amethyl group. When there is more than one substituent present on the ring, their spatial relationship becomes important for which thearene substitution patternsortho,meta, andpara are devised.[9] When reacting to form more complex benzene derivatives, the substituents on a benzene ring can be described as eitheractivated ordeactivated, which are electron donating and electron withdrawing respectively.[9] Activators are known as ortho-para directors, and deactivators are known as meta directors.[9] Upon reacting, substituents will be added at the ortho, para or meta positions, depending on the directivity of the current substituents to make more complex benzene derivatives, often with several isomers. Electron flow leading to re-aromatization is key in ensuring the stability of such products.[9]
For example, threeisomers exist forcresol because the methyl group and the hydroxyl group (both ortho para directors) can be placed next to each other (ortho), one position removed from each other (meta), or two positions removed from each other (para).[10] Given that both the methyl and hydroxyl group are ortho-para directors, the ortho and para isomers are typically favoured.[10]Xylenol has two methyl groups in addition to the hydroxyl group, and, for this structure, 6 isomers exist.[citation needed]
Arene rings can stabilize charges, as seen in, for example, phenol (C6H5–OH), which isacidic at the hydroxyl (OH), as charge on the oxygen (alkoxide –O−) is partially delocalized into the benzene ring.
Although benzylic arenes are common, non-benzylic compounds are also exceedingly important. Any compound containing a cyclic portion that conforms toHückel's rule and is not a benzene derivative can be considered a non-benzylic aromatic compound.[5]
Ofannulenes larger than benzene, [12]annulene and [14]annulene are weakly aromatic compounds and [18]annulene,Cyclooctadecanonaene, is aromatic, though strain within the structure causes a slight deviation from the precisely planar structure necessary for aromatic categorization.[11] Another example of a non-benzylic monocyclic arene is thecyclopropenyl (cyclopropenium cation), which satisfiesHückel's rule with an n equal to 0.[12] Note, only the cationic form of this cyclic propenyl is aromatic, given that neutrality in this compound would violate either the octet rule orHückel's rule.[12]
Other non-benzylic monocyclic arenes include the aforementioned heteroarenes that can replace carbon atoms with other heteroatoms such as N, O or S.[5] Common examples of these are the five-memberedpyrrole and six-memberedpyridine, both of which have a substituted nitrogen.[13]
Polycyclic aromatic hydrocarbons, also known as polynuclear aromatic compounds (PAHs) are aromatic hydrocarbons that consist of fusedaromaticrings and do not containheteroatoms or carrysubstituents.[14]Naphthalene is the simplest example of a PAH. PAHs occur inoil,coal, andtar deposits, and are produced as byproducts of fuel burning (whether fossil fuel or biomass).[15] As pollutants, they are of concern because some compounds have been identified ascarcinogenic,mutagenic, andteratogenic.[16][17][18][19] PAHs are also found in cooked foods.[15] Studies have shown that high levels of PAHs are found, for example, in meat cooked at high temperatures such as grilling or barbecuing, and in smoked fish.[15][16] They are also a goodcandidate molecule to act as a basis for the earliest forms of life.[20] Ingraphene the PAH motif is extended to large 2D sheets.[21]
Aromatic ring systems participate in many organic reactions.
In aromaticsubstitution, onesubstituent on the arene ring, usually hydrogen, is replaced by another reagent.[5] The two main types areelectrophilic aromatic substitution, when the active reagent is an electrophile, andnucleophilic aromatic substitution, when the reagent is a nucleophile. Inradical-nucleophilic aromatic substitution, the active reagent is aradical.[22][23]
An example ofelectrophilic aromatic substitution is the nitration ofsalicylic acid, where a nitro group is added para to the hydroxide substituent:
Nucleophilic aromatic substitution involves displacement of aleaving group, such as ahalide, on anaromatic ring. Aromatic rings usually nucleophilic, but in the presence ofelectron-withdrawing groups aromatic compounds undergo nucleophilic substitution. Mechanistically, this reaction differs from a commonSN2 reaction, because it occurs at a trigonal carbon atom (sp2hybridization).[24]
Hydrogenation of arenes create saturated rings. The compound1-naphthol is completely reduced to a mixture ofdecalin-olisomers.[25]
The compoundresorcinol, hydrogenated withRaney nickel in presence of aqueoussodium hydroxide forms anenolate which is alkylated withmethyl iodide to 2-methyl-1,3-cyclohexandione:[26]
Indearomatization reactions the aromaticity of the reactant is lost. In this regard, the dearomatization is related to hydrogenation. A classic approach isBirch reduction. The methodology is used in synthesis.[27]
Arene-arene interactions have attracted much attention. Pi-stacking (also calledπ–π stacking) refers to the presumptively attractive,noncovalentpi interactions between thepi bonds ofaromatic rings, because oforbital overlap.[29] According to some authors direct stacking of aromatic rings (the "sandwich interaction") iselectrostatically repulsive.
More commonly observed are either astaggered stacking (parallel displaced) orpi-teeing (perpendicular T-shaped) interaction both of which are electrostatic attractive[30][31] For example, the most commonly observed interactions between aromatic rings of amino acid residues in proteins is a staggered stacked followed by a perpendicular orientation. Sandwiched orientations are relatively rare.[32]
Pi stacking is repulsive as it places carbon atoms with partial negative charges from one ring on top of other partial negatively charged carbon atoms from the second ring and hydrogen atoms with partial positive charges on top of other hydrogen atoms that likewise carry partial positive charges.[30] In staggered stacking, one of the two aromatic rings is offset sideways so that the carbon atoms with partial negative charge in the first ring are placed above hydrogen atoms with partial positive charge in the second ring so that the electrostatic interactions become attractive. Likewise, pi-teeing interactions in which the two rings are oriented perpendicular to either other is electrostatically attractive as it places partial positively charged hydrogen atoms in close proximity to partially negatively charged carbon atoms. An alternative explanation for the preference for staggered stacking is due to the balance betweenvan der Waals interactions (attractivedispersion plusPauli repulsion).[33]
These staggered stacking and π-teeing interactions between aromatic rings are important innucleobase stacking withinDNA andRNA molecules,protein folding,template-directed synthesis,materials science, andmolecular recognition. Despite the wide use of term pi stacking in the scientific literature, there is no theoretical justification for its use.[30]
Thebenzene dimer is the prototypical system for the study of pi stacking, and is experimentally bound by 8–12 kJ/mol (2–3 kcal/mol) in the gas phase with a separation of 4.96 Å between the centers of mass for the T-shaped dimer.[34]X-ray crystallography reveals perpendicular and offset parallel configurations for many simple aromatic compounds.[34] Similar offset parallel or perpendicular geometries were observed in a survey of high-resolution x-ray protein crystal structures in theProtein Data Bank.[35] Analysis of the aromatic amino acids phenylalanine, tyrosine, histidine, and tryptophan indicates that dimers of these side chains have many stabilizing interactions at distances larger than the average van der Waals radii.[32]
The relative binding energies of the three geometries of the benzene dimer can be explained by a balance of quadrupole/quadrupole andLondon dispersion forces. While benzene does not have a dipole moment, it has a strongquadrupole moment.[36] The local C–H dipole means that there is positive charge on the atoms in the ring and a correspondingly negative charge representing an electron cloud above and below the ring. The quadrupole moment is reversed forhexafluorobenzene due to the electronegativity of fluorine. The benzene dimer in the sandwich configuration is stabilized by London dispersion forces but destabilized by repulsive quadrupole/quadrupole interactions. By offsetting one of the benzene rings, the parallel displaced configuration reduces these repulsive interactions and is stabilized. The large polarizability of aromatic rings lead todispersive interactions as major contribution to stacking effects. These play a major role for interactions of nucleobases e.g. inDNA.[37] The T-shaped configuration enjoys favorable quadrupole/quadrupole interactions, as the positive quadrupole of one benzene ring interacts with the negative quadrupole of the other. The benzene rings are furthest apart in this configuration, so the favorable quadrupole/quadrupole interactions evidently compensate for diminisheddispersion forces.
According to one model, electron-withdrawing substituents lowers the negative quadrupole of the aromatic ring and thereby favor parallel displaced and sandwich conformations. By contrast, electron donating groups increase the negative quadrupole, which may stabilize a T-shaped configuration with the proper geometry.[38] They used a simple mathematical model based on sigma and pi atomic charges, relative orientations, and van der Waals interactions to qualitatively determine thatelectrostatics are dominant in substituent effects.[39]
Hunteret al. applied a more sophisticated chemical double mutant cycle with a hydrogen-bonded "zipper" to the issue of substituent effects in pi stacking interactions in proteins.[40][41] However, the authors note that direct interactions with the ring substituents, discussed below, also make important contributions. Indeed, the interplay of these two factors may result in the complicated substituent- and geometry-dependent behavior of pi stacking interactions.
Some experimental and computational evidence suggests that pi stacking interactions are not governed primarily by electrostatic effects.[42][43]
The relative contributions pi stacking have been borne out by computation.[44][45][46] Trends based on electron donating or withdrawing substituents can be explained by exchange-repulsion and dispersion terms.[47]
A molecular torsion balance from an aryl ester with two conformational states.[48] The folded state had a well-defined pi stacking interaction with a T-shaped geometry, whereas the unfolded state had no aryl–aryl interactions. The NMR chemical shifts of the two conformations were distinct and could be used to determine the ratio of the two states, which was interpreted as a measure of intramolecular forces. The authors report that a preference for the folded state is not unique to aryl esters. For example, the cyclohexyl ester favored the folded state more so than the phenyl ester, and the tert-butyl ester favored the folded state by a preference greater than that shown by any aryl ester. This suggests that aromaticity is not a strict requirement for favorable interaction with an aromatic ring.
Other evidence for non-aromatic pi stacking interactions results include critical studies in theoretical chemistry, explaining the underlying mechanisms of empirical observations.Grimme reported that the interaction energies of smaller dimers consisting of one or two rings are very similar for both aromatic and saturated compounds.[49] This finding is of particular relevance to biology, and suggests that the contribution of pi systems to phenomena such as stacked nucleobases may be overestimated. However, it was shown that an increased stabilizing interaction is seen for large aromatic dimers. As previously noted, this interaction energy is highly dependent on geometry. Indeed, large aromatic dimers are only stabilized relative to their saturated counterparts in a sandwich geometry, while their energies are similar in a T-shaped interaction.
A more direct approach to modeling the role of aromaticity was taken by Bloom and Wheeler.[50] The authors compared the interactions between benzene and either 2-methylnaphthalene or its non-aromatic isomer, 2-methylene-2,3-dihydronaphthalene. The latter compound provides a means of conserving the number of p-electrons while, however, removing the effects of delocalization. Surprisingly, the interaction energies with benzene are higher for the non-aromatic compound, suggesting that pi-bond localization is favorable in pi stacking interactions. The authors also considered ahomodesmotic dissection of benzene into ethylene and 1,3-butadiene and compared these interactions in a sandwich with benzene. Their calculation indicates that the interaction energy between benzene and homodesmotic benzene is higher than that of a benzene dimer in both sandwich and parallel displaced conformations, again highlighting the favorability of localized pi-bond interactions. These results strongly suggest that aromaticity is not required for pi stacking interactions in this model.
Even in light of this evidence, Grimme concludes that pi stacking does indeed exist.[49] However, he cautions that smaller rings, particularly those in T-shaped conformations, do not behave significantly differently from their saturated counterparts, and that the term should be specified for larger rings in stacked conformations which do seem to exhibit a cooperative pi electron effect.
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