Chapter 11. Aromatic Compounds
Recommended Post: 【Organic Chemistry】 Organic Chemistry Table of Contents
1. Aromaticity
2. Benzene Derivatives Nomenclature
4. Reaction 1. Electrophilic Aromatic Substitution
5. Reaction 2. Nucleophilic Aromatic Substitution
6. Reaction 3. Other Reactions
8. Aromatic Side Chain Effects
1. Aromaticity
⑴ Aromaticity: Having much lower energy than expected, with significantly altered reactivity which is related to aromatic substituent effect.
⑵ Hückel’s rule: Aromaticity is achieved if four conditions are met
① Ring structure
○ Reason: Ring structures facilitate overlap of p orbitals
② Planar structure
○ cyclooctatetraene is not planar, hence not aromatic
○ However, treating cyclooctatetraene with 2eq K leads to a planar structure with 10 π electrons
③ All atoms forming the planar ring must satisfy conjugation
④ The number of π electrons in p orbitals must be 4n + 2, where n = 0, 1, 2, ···
○ Tied to the conditions for forming planar rings (e.g., cyclooctatetraene is not planar, so not aromatic)
○ 2π systems have ring strain, so 6π systems are more common
⑶ Frost’s Circle (polygon rule)
① Draw an inscribed circle for a given ring structure
② The MO located below relative to the center of the circle is the bonding MO, the MO located above is the antibonding MO, and the one at the center height is the nonbonding MO.
③ Aromaticity is satisfied if there are no electrons in the antibonding MO and no unpaired electrons.
⑷ Examples
Figure 1. Benzene, Pyridine, Pyrrole
① Benzene: Satisfies Hückel’s rule
② Pyridine: Satisfies Hückel’s rule. Nitrogen’s lone electron pairs do not participate in resonance, acting as a weak base
③ Pyrrole: Satisfies Hückel’s rule. Nitrogen’s lone electron pair participates in resonance, lacking basicity
⑸ Anti-aromaticity, Non-aromaticity
① Anti-aromaticity: Only the π electron count condition changes from 4n+2 to 4n in Hückel’s rule, thus not satisfying Hückel’s rule and not having aromaticity.
② Cyclooctatetraene has 4n π electrons (n=2), but not all carbons lie in the same plane, making it non-aromatic, not anti-aromatic.
③ Possessing aromaticity results in substitution reactions only, while possessing antiaromaticity or non-aromaticity leads to addition reactions only, similar to alkenes
⑹ Python code to determine aromaticity
from rdkit import Chem
def is_aromatic(smiles):
molecule = Chem.MolFromSmiles(smiles)
if molecule is None:
return False
return any(atom.GetIsAromatic() for atom in molecule.GetAtoms())
# Example usage
cyclohexane = "C1CCCCC1" # cyclohexane
benzene = "c1ccccc1" # benzene
imidazole = "C1=CN=CN1" # 1H-imidazole
print(f"The {cyclohexane} is {'aromatic' if is_aromatic(cyclohexane) else 'not aromatic'}")
print(f"The {benzene} is {'aromatic' if is_aromatic(benzene) else 'not aromatic'}")
print(f"The {imidazole} is {'aromatic' if is_aromatic(imidazole) else 'not aromatic'}")
2. Benzene Derivatives Nomenclature
⑴ Substituent Naming
⑵ Numbering
① If there is only one substituent, no number is assigned.
② Arrange the numbers so that the carbon atom with the higher priority functional group has the lower number.
○ The carbon atom with the highest priority functional group is numbered as 1.
③ If multiple numberings are possible, assign the numbers in a way that the carbon atoms with the same priority functional groups have the fewest numbers.
④ Even so, if multiple cases are possible, substituents should be numbered in alphabetical order, giving the lower numbers to the substituents that come first alphabetically.
Figure 2. 1-Bromo-2-chloro-4-ethyl-5-nitrobenzene
⑤ For 1,2-substitution, use ortho(o-); for 1,3-substitution, use meta(m-); for 1,4-substitution, use para(p-).
⑶ Suffix Naming: Use common names approved by IUPAC
① If the main functional group is a carboxylic acid (-COOH): 《··· + benzoic acid》
② If the main functional group is an aldehyde (-CHO): 《··· + benzaldehyde》
③ If the main functional group is -COMe: 《··· + acetophenone》
④ If the main functional group is a hydroxyl group (-OH): 《··· + phenol》
⑤ If the main functional group is an amino group (-NH2): 《··· + aniline》
⑥ If the main functional group is an ether (-OMe): 《··· + anisol》
⑦ If the main functional group is a methyl group (-CH3): 《··· + toluene》
⑧ Others: chlorobenzene, styrene, t-butylbenzene, o-xylene, m-xylene, cumene, nitrobenzene, benzonitrile, mesitylene, o-cresol, m-cresol
⑷ Full Name Naming
① Rearrange groups with equal priority in alphabetical order
② Name as 《(substituent position-substituent name)n + main chain + suffix》
⑸ When Benzene Rings are Treated as Substituents
① If the number of carbon atoms in the alkyl substituent is less than that in benzene, the alkyl group is treated as a substituent.
② If the alkyl substituent has equal or more carbons than benzene, treat benzene as the substituent and express it as phenyl(= Ph, Φ)
○ Example: 2-phenylhexane (= n -hexylbenzene)
③ If higher-priority functional groups like alkenes are present, benzene is treated as the substituent
⑹ Naphthalene, Anthracene, Phenanthrene Nomenclature
Figure 3. Naphthalene Nomenclature
Figure 4. Anthracene Nomenclature
Figure 5. Phenanthrene Nomenclature
⑺ Heteroaromatic Nomenclature
Figure 6. Pyrrole Nomenclature
Figure 7. Imidazole Nomenclature
Figure 8. Furan Nomenclature
Figure 9. Pyridine Nomenclature
Figure 10. Thiophene Nomenclature
Figure 11. Pyrimidine Nomenclature
Figure 12. Quinoline Nomenclature
Figure 13. Isoquinoline Nomenclature
Figure 14. Dibenzo-p-dioxin Nomenclature
Figure 15. Azulene Nomenclature
Figure 16. Fluorene Nomenclature
Figure 17. Benzofuran Nomenclature
3. Benzene Properties
⑴ Kekulé Structure: Single and double bonds are interchangeable, with all bond lengths being the same
① C-C single bond length: 154 pm
② C=C double bond length: 134 pm
③ Benzene’s carbon-carbon bond length: 139 pm, all carbon-carbon bond lengths are the same
⑵ Lower-than-expected Hydrogenation Enthalpy
Figure 18. Benzene’s Lower-than-Expected Hydrogenation Enthalpy
① Cyclohexene has 28.6 kcal/mol (= 118 kJ/mol) more energy than cyclohexane.
② 1,3-cyclohexadiene has 230 kJ/mol more energy than cyclohexane.
③ The mismatch between 230 kJ/mol and 236 kJ/mol (= 118 × 2) arises from resonance stabilization.
④ Benzene has 49.8 kcal/mol (= 206 kJ/mol) more energy than cyclohexane.
⑤ 36 kcal/mol (= 152 kJ/mol) in the figure above represents benzene’s resonance stabilization energy
⑶ Low Reactivity of Benzene: Unlike alkenes or alkynes, benzene’s reactions are difficult to initiate
① Exception 1. Reaction under high temperature and pressure to form cyclohexane
○ H2 / Ni
○ H2, Pt, ethanol, 130 atm, 25 ℃
○ H2, Rh / C, ethanol, 1 atm, 25 ℃
② Exception 2. Exception 2: Catalytic Deuteration Reaction: Under high temperature and pressure, benzene reacts with D2, Rh / C conditions, leading to syn addition of deuterium atoms to benzenes.
⑷ Benzene’s Stability: When substituents donate electrons, benzene becomes unstable; when withdrawing, it becomes more stable
Figure 19. Benzene, Nitrobenzene
① Example: Nitrobenzene is more stable than benzene and at a lower energy level
4. Reaction 1. Electrophilic Aromatic Substitution
⑴ Overview: Halogenation, Sulfonation, Nitration, Acylation, Alkylation, Peroxide
① Abbreviated as EAS.
② Benzene is a weak nucleophile
③ Electrophilic reactions proceed using highly reactive electrophiles E+
○ Formation of arenium ion E+ is the rate-determining step
④ E+ is generated within the reaction system using a catalyst
⑤ Tendency 1. Benzene rings perform better in EAS as electron density increases
○ In isoquinoline, the carbons in the ring containing nitrogen have a lower electron density, so reactions occur first in the aromatic ring without nitrogen.
⑥ Tendency 2. benzene ＜ thiophene ＜ furan ＜ pyrrole
○ Aromaticity: benzene ＞ thiophene ＞ pyrrole ＞ furan
⑵ Reaction 1. Halogenation
① 1-1. Benzene Halogenation: (Formula) X2 + FeX3 → FeX4- + X+
Figure 20. Benzene Halogenation Mechanism
○ Fluorination: Reaction is very fast. Using F-TEDA-BF4 as a reagent can improve the reaction
○ Iodination: Reaction is slow. Treating with nitric acid can enhance aromatic compounds’ electrophilicity.
② 1-2. Furan Halogenation: Reaction under dioxane / 0 ℃
○ The reason ortho orientation is dominant over para orientation is because ortho orientation has a greater number of resonance contributors.
Figure 21. Furan Halogenation
③ 1-3. NBS and NIS-mediated directional halogenation reaction: NBS and NIS act as Br and I donors, respectively.
⑶ Reaction 2. Sulfonation
① 2-1. Benzene Sulfonation: (Formula) H2SO4 + H2SO4 → SO3H+ + HSO4- + H2O
○ Catalyst: SO3 is used
Figure 22. Benzene Sulfonation Mechanism
② 2-2. Sulfonation of furan: Proceeds with pyridine / ethylene chloride at 100°C
Figure 23. Sulfonation of furan
○ The reason ortho orientation is dominant over para orientation is because ortho orientation has a greater number of resonance contributors.
③ Features
○ The only Electrophilic Aromatic Substitution (EAS) reaction that is reversible: This allows it to be used as a protective reaction for aromatic compounds from EAS.
○ Sulfonation reactions proceed in concentrated H2SO4.
○ Desulfonation reactions occur in dilute H2SO4.
○ Alkali fusion: In benzene with a sulfonyl group, under NaOH and heat conditions, the SO3H group is replaced by SO3, and an OH group is attached instead.
⑷ Reaction 3. Nitration
① 3-1. Benzene Nitration: (Formula) HONO2 + H2SO4 → NO2+ + HSO4- + H2O
○ Reaction proceeds well in high-concentration H2SO4 and HNO3
○ Reaction can also be achieved using NO2BF4 reagent other than HNO3 / H2SO4
○ (Formula 1) H2 / Pd converts -NO2 group to -NH2 group
○ (Formula 2) Sn / HCl converts -NO2 group to -NH2 group
○ Organic Chemistry Experiment
○ Initially, introduce concentrated nitric acid and concentrated sulfuric acid, then cool to room temperature and open the reflux apparatus
○ Adjust the temperature to suppress dinitration
Figure 24. Benzene Nitration Mechanism
② 3-2. Furan Nitration: Reaction under HNO3 / anhydride
Figure 25. Furan Nitration
⑸ Reaction 4. Friedel-Crafts Acylation
① Overview: Acyl groups are denoted as RCO-
② 4-1. Benzene Acylation: (Formula) RCOCl + AlCl3 → RCO+ + AlCl4-
Figure 26. Benzene Acylation Mechanism
○ AlCl3 is consumed and not used as a catalyst
○ The vinyl carbocation (acylium ion) is highly unstable and rapidly interconverts through a different resonance structure
Figure 27. Resonance of Vinyl Carbocation
③ 4-2. Furan Acylation: Reaction under anhydride / BF3
Figure 28. Furan Acylation
④ 4-3. Synthesis of Fluorescein: Reaction between phthalic anhydride and 2 × resorcinol → fluorescein (Catalyst: ZnCl2)
Figure 29. Synthesis of Fluorescein
⑤ 4-4. Gattermann-Koch Reaction
○ It is not feasible to introduce a formyl group (-CHO) into benzene through ordinary Friedel-Crafts acylation
○ Under pressure with HCl and Lewis acid, benzene can react with CO, resulting in the formyl group substitution.
⑥ 4-5. Blanc Chloromethylation
○ Reactants: Benzene, HCHO
○ Reagents: HCl, ZnCl2
○ Product: 1-(chloromethyl)benzene
⑦ 4-6. Fries rearrangement reaction
○ phenol + RCOCl: O-acylation
○ phenol + RCOCl + AlCl3: C-acylation (Friedel-Crafts acylation)
○ The Fries rearrangement reaction converts O-acylated products into C-acylated products through rearrangement reactions.
⑧ Limitations
○ Problem 1: Vinyl halides and aryl halides cannot act as substrates: Carbocations are highly unstable, leading to low reactivity.
○ Problem 2: Aromatic rings substituted with a strong electron-withdrawing group (EWG) do not undergo acylation reactions.
○ Problem 3: Exceptionally, despite the substitution of an EDG, aniline does not undergo the reaction.
○ Reason: The -NH2 group in aniline is transformed into -N+H2AlCl3 through reaction with AlCl3 and acid, becoming a strong EWG.
⑹ Reaction 5: Friedel-Crafts Alkylation
① (Reaction) RCl + AlCl3 → R+ + AlCl4-
② Mechanism
Figure 30. Mechanism of benzene alkylation
○ Rearrangement reaction can proceed like R+ → R*+.
○ For secondary and tertiary alkyl fluorides, SbF<sub5</sub> (antimony pentafluoride, super acid) is used instead of AlCl3.
③ Limitations
○ Problem 1: Rearrangement reaction: Friedel-Crafts acylation does not involve rearrangement reactions.
○ Problem 2: Vinyl halides and aryl halides cannot act as substrates: Carbocations are highly unstable, leading to low reactivity.
○ Problem 3: Aromatic rings with strong electron-withdrawing groups (EWG) do not undergo alkylation and acylation.
○ Problem 4: Aniline, despite being an electron-donating group (EDG), does not undergo the reaction.
○ Reason: The -NH2 group in aniline is transformed into -N+H2AlCl3 through reaction with AlCl3 and acid, becoming a strong EWG.
○ Problem 5: Multiple alkylation reactions: This is because the EAS reactivity of benzene increases as more alkyl groups are added.
⑺ Reaction 6: Friedel-Crafts Arylation
① (Reaction) Removal of -OH group and attachment of an aromatic ring
Figure 31. CF3SO3H Friedel-Crafts arylation
⑻ Reaction 7: SnCl4-catalyzed EAS
Figure 32. SnCl4-catalyzed EAS
⑼ Reaction 8: Peroxides (e.g., (CH3CO)2O (acetic anhydride))
⑽ Reaction 9: Other carbon-carbon coupling reactions
① Carbon-carbon coupling reactions using organic metal reagents
○ Grignard reagent
○ Alkyl lithium reagent
○ Gilman reagent
② Stille coupling: Palladium catalyst, organic tin
③ Negishi coupling: Palladium catalyst, organic zinc
④ Heck coupling (Heck reaction)
○ (Reaction) When a haloalkene or haloarene reacts with vinyl-H (i.e., the hydrogen attached to the alkene) under palladium catalyst and base, the vinyl-H undergoes substitution with an R-group, with the release of HX. For instance, if the reactant were a haloarene, then the phenyl group would be substituted.
Figure 33. Heck coupling
○ Substrates: vinyl halides, aryl halides, heterocyclic halides, benzylic halides, trifluoromethanesulfonate (CF3SO2O, triflate)
○ Palladium catalysts: Pd(OAc)2 (most commonly used), P(o-tolyl)3, (CH3CH2)3N, etc.
○ Bases: Et3N, NaOAc, NaHCO3, KOAc
○ Solvents: Polar aprotic solvents such as DMF, CH3CN, DMSO to dissolve Pd(OAc)2.
○ Ligands: Ph3P is commonly used as a ligand for coordinating with Pd(0)
○ Mechanism: Formation of square planar Pd(Ⅱ) intermediate
○ High regioselectivity: Occurs predominantly at the less substituted side of the vinyl-H (due to steric effect)
○ High stereoselectivity: Only trans products are obtained
○ Reactivity of halides: I > Br > Cl
○ Faster reaction and higher yield with less substitution on the double bond (due to steric effect)
⑤ Suzuki coupling
○ (Formula) Organic boron reagents react with alkyl halides under Palladium catalysts and base in the form of in carbon-carbon coupling reactions.
○ Halogenated Alkyl: vinyl halide (triflate), alkynyl halide, aryl halide.
○ Palladium Catalyst: biaryl phosphine ligand XPhos (XPhos Pd G4), etc.
○ Mechanism: Consists of three stages - oxidative addition (fast), transmetalation (slow), reductive elimination (slow).
Figure 34. Suzuki Coupling Mechanism
○ Example 1. Application of Grignard Coupling and Suzuki Coupling:
Figure 35. Application of Grignard Coupling and Suzuki Coupling
○ Example 2. Suzuki Coupling of Aryl Boronic Acid and Aryl Bromide:
Figure 36. Suzuki Coupling of Aryl Boronic Acid and Aryl Bromide.
⑥ Hiyama coupling: Palladium catalyst, organic silane
⑦ Kumada coupling: Palladium catalyst, Grignard reagents
⑧ Yamada coupling
⑾ Reaction 10: Other carbon-nitrogen coupling reactions
① Coupling reaction between aniline derivative and aryl bromide under palladium catalyst
○ Palladium catalysts: AlPhos-ligated palladium dimer, etc.
○ Other conditions: DBU in THF at 50°C
Figure 37. Coupling reaction between aniline derivative and aryl bromide under palladium catalyst
5. Reaction 2. Nucleophilic Aromatic Substitution (SNAr) Reactions
⑴ Overview
① Not SN2-like
○ Reason 1: Phenyl groups create steric hindrance.
○ Reason 2: Halogen groups exhibit double-bond-like character due to resonance.
○ Reason 3: sp2 carbons have strong bonding strength.
② Not SN1-like: Phenyl cations are unstable.
⑵ Reaction 1: Elimination Reaction after Addition
① 1-1. General addition-elimination reaction
Figure 38. Addition-elimination reaction
○ Addition of a nucleophile to the halogen position followed by the release of the halogen group.
○ The intermediate is called meisenheimer.
○ Formation of meisenheimer is the rate-determining step
○ Reaction occurs more readily when EWGs are oriented in ortho or para positions, compared to EAS.
○ Comparison of reaction rates for halogen groups: Larger electronegativity stabilizes the intermediate due to electron-withdrawing effect.
○ F ≫ Cl > Br ≫ I
② 1-2. Chichibabin reaction
⑶ Reaction 2: Addition Reaction after Elimination: Formation of Benzyne
① 2-1. General elimination-addition reaction
Figure 39. Elimination-addition reaction
○ Characteristics of benzyne
○ Carbons participating in triple bonds have intermediate characteristics of sp and sp2 hybridization.
○ If a carbon with sp hybridization is present, it forms a linear structure due to VSEPR, resulting in ring strain and antiaromaticity.
○ Therefore, benzyne’s triple bond consists of 1 π bond, 1 σ bond, and 1 additional σ bond.
○ Thus, when benzene is formed from an alkene, the newly formed π bond results from the overlap of sp2-sp2 orbitals.
Figure 40. Concept of benzyne bonding
○ Addition of bases to halogenated benzene results in the formation of benzyne.
○ Commonly used bases: KNH2, NaNH2
○ Characteristics of addition reaction after elimination
○ Formation of benzyne intermediate is the rate-determining step.
○ Observation of kinetic isotope effect is possible due to difficulty in removing hydrogen.
○ The reaction rate increases as the halogen element becomes easier to leave as a leaving group.
○ F ＜ Cl ＜ Br ＜ I
○ For benzynes, the determination of nucleophilic and electrophilic carbons considers only the electron-donating or electron-withdrawing inductive effect of the substituents.
○ Example: -OMe is an electron-donating group (EDG), but when assessing the stability of benzyne, there is no resonance effect, so it is considered an electron-withdrawing group (EWG) due solely to the inductive effect.
○ Substituents emerge in the meta orientation to the EWG.
○ Addition reaction after elimination in the case of benzene with two substituents
○ When the two substituents are ortho or meta: meta substitution.
○ When the two substituents are para: para substitution in the case of electron-withdrawing effects, meta substitution in the case of electron-donating effects.
② 2-2. Diels-Alder reaction in benzyne
③ 2-3. Other methods for synthesizing benzyne
○ Fluoride sources: CsF, TBAF, TBAT, TMAF
○ Mg / THF
○ Applying denitrification reactions
6. Reaction 3. Other Reactions
⑴ Electrophilic Aromatic Addition Reactions
① As the ring size increases, the amount of lost resonance stabilization energy per ring decreases, making addition reactions possible.
② Anthracene and phenanthrene can undergo electrophilic aromatic addition reactions at positions 9 and 10.
⑵ Aromatic Side-Chain Oxidation Reactions
① (Reaction 1) 1. KMnO4, OH-, Δ, 2. H+: Conversion of hydrogen-bearing benzyl carbons to -COOH
② (Reaction 2) KMnO4, Na2Cr2O7, H2Cr2O7, H2ClO4: Conversion of hydrogen-bearing benzyl carbons to -COOH
③ (Reaction 3) CF3CO3H: Oxidation of amino group to nitro group
⑶ Aniline
① Diazotization Reaction
○ (Reaction 1) Aniline reacts with HNO2 / H2SO4 to form diazobenzene (functional group: -N2+).
○ (Reaction 2) Aniline + NaNO2, HCl, 0 ℃ → diazobenzene
○ Mechanism
Figure 41. Mechanism of diazotization reaction
○ Notably forms nitrosonium ion (+N=O) as an intermediate
○ Different from nitration conditions HNO3 / H2SO4
○ Reaction 1. Sandmeyer reaction
○ Ph-N2+ + CuBr → Ph-Br + N2 (g)
○ Ph-N2+ + KI → Ph-I + N2 (g)
○ Ph-N2+ + CuC≡N → Ph-C≡N + N2 (g)
○ Ph-N2+ + H3O+ → Ph-OH + HCl + N2 (g) (conditions: Δ)
○ Ph-N2+ + CuCl → Ph-Cl + N2 (g)
○ Ph-N2+ + Cu2O, Cu(NO3)2, H2O → Ph-OH + N2 (g)
○ Ph-N2+ + H3PO2 → benzene + N2 (g)
○ Reaction 2. Schiemann reaction
○ Ph-N2+ + HBF4 → Ph-F + BF3 + N2 (g) (conditions: Δ)
② Acetylation Reaction
○ -NH2 group is a strong EDG, allowing reaction with anhydrides (R-CO-O-CO-R) without a catalyst.
○ Results in the formation of acetanilide, which is an amide.
○ Benefit 1. Protection of -NH2 group
○ Benefit 2. Decreased reactivity of aniline: Aniline is highly reactive, producing 3-substituted products in halogenation reactions.
○ Conversion to -NH2 group under conditions 1. H3O+, Δ, 2. NaOH
○ Under conditions 1, amide hydrolysis occurs, producing -NH3+ group.
○ Under conditions 2, conversion to -NH2 group using NaOH.
⑷ Birch Reduction
① Reagents: 1. Alkali metals (Na, Li, etc.), NH3 (acts as an acid), 2. ROH (acts as an acid)
② Mechanism
Figure 42. Birch reduction mechanism
○ Alkali metals react vigorously with water to become ions.
○ A radical electron is released, which enters the benzene ring, followed by resonance.
○ Another electron enters, and NH3 acts as an acid in a unique way to recover the two radical electrons.
○ Subsequently, ROH-catalyzed tautomerization may occur.
③ (Reaction 1) Adjust the position of double bonds so that two opposite points on the benzene ring become sp3.
④ (Reaction 2) The position becoming sp3 should be located with an EWG and not an EDG.
○ In the mechanism, a carbocation forms on a site without a double bond.
⑤ (Reference) It has a similar reaction condition to Anti Addition Reaction of Alkynes
⑸ Williamson Ether Synthesis of Phenols
① (Reaction) CH3I, OH- conditions lead to substitution of -OH group with -OCH3 group
⑹ Substituent Reduction Reaction
① Clemmensen Reduction
○ (Formula 1) Zn, Fe, Ni, Hg or SnCl2 / HCl conditions reduce NO2, ketones, aldehydes on benzyl position to NH2, CH2.
○ (Formula 2) H2, Pt conditions reduce NO2, ketones, aldehydes on benzyl position to NH2, CH2.
○ Ketones: Oxygen of C=O attaches to Zn → HCl donates a proton to carbon → Zn oxidizes and provides electrons to oxygen → reduction
○ Resonance-stabilized alkenes cannot be reduced.
○ Carboxylic acids and esters cannot be reduced.
Figure 43. Example of Clemmensen reduction
② Wolff-Kishner reduction: Reduction of acyl substituents to alkyl substituents.
③ thioacetal + H2 / Raney-Ni (desulfurization): Reduction of acyl substituent to alkyl substituent
④ H2S, NH3, C2H5OH: Can reduce m-dinitrobenzene to m-nitroaniline
⑺ Reaction between benzene and hydrogen peroxide
① benzene + CF3SO3H + H2O2 → phenol
⑻ Claisen Rearrangement Reaction: Allyl phenyl ether participates as a reactant
⑼ Phenol oxidation reaction
① Benzene can be oxidized to benzoquinone using Fremy salts ((KSO3)2NO)
⑽ Quinone reduction reaction
① Using NaBH4, SnCl2, coenzyme Q, phenol can be reduced to hydroquinone
7. Substituent Effects
⑴ Substituent groups: The concept of substituent groups is not limited to aromatic compounds only
① Strong activating substituents: -NH2, -NHR, -NR2, -OH, -O-
○ Groups with lone pairs of electrons
② Moderate activating substituents: -NHCOCH3, -NHCOR, -OCOCH3, -OCH3, -OR
○ Groups with lone pairs of electrons, but also have significant electron-withdrawing effects
③ Weak activating substituents: -R, -Phe
○ Groups that donate electrons
④ -H: Benzene
⑤ Weak deactivating substituents: -X
○ Halogen groups
⑥ Moderate deactivating substituents: -C≡N, -SO3H, -CO2H, -CO2R, -CHO, -COR
○ Acetyl group (-COR) is weaker EWG than nitrile group (-C≡N) or sulfone group (-SO3H)
⑦ Strong deactivating substituents: -CF3, -CCl3, -NO2, -N+R3
○ Have positive charge or -CF3 group
○ -CF3 and -NR3 have weak electron-withdrawing abilities as EWG, but they are highly effective at reducing reactivity.
⑵ Activating substituents (EDG, electron-donating group): ortho substitution , para substitution
① Strong/Moderate activating substituents
○ Electron-donating Resonance effect > Electron-withdrawing Inductive effect: Donate electrons to the reactant benzene, causing instability and increasing reactivity.
○ In the case of intermediates, they stabilize carbocation by donating electrons
○ React rapidly due to low activation energy
② Weak activating substituents: Donate electrons to the reactant benzene, causing instability and increasing reactivity.
⑶ Deactivating substituents (EWG, electron-withdrawing group)
① Halogen groups: ortho substitution, para substitution
○ Electron-withdrawing Inductive effect > Electron-donating Resonance effect
○ F: Strong electronegativity leads to stronger electron-withdrawing inductive effect than electron-donating resonance effect → Deactivation
○ Cl, Br, I: Poor resonance effect of lone pairs of electrons due to poor overlap of p orbitals by the difference of periods of atoms. For example, Cl in 3rd period will interact with carbons in the 2nd period, resulting in 2p-3p orbital interactions and decreasing the resonance effect compared to 2p-2p interactions.
○ Fluorobenzene is more electrophilic than other halobenzenes: The importance of p-p orbital overlap!
○ F > Cl > Br > I in terms of both EAS and SNAr reactivity.
○ Halogen groups are considered as EDGs under certain conditions
○ When comparing reaction rates among various benzene derivatives, halogen groups are considered as EWGs, leading to slower reactions
○ When determining major product from halobenzene, ortho or para isomers are obtained as major products, like EDGs
○ Reason: Electron-donating resonance effect from lone pairs in halogen induces major production of ortho or para isomers
○ When halogen group is competing with R group, major product comes from ortho or para isomer of the halogen group, independent from the position of R group.
○ Reason: Under conditions where the halogen group is considered as an EDG, electron-donating effect is better than R group
② Strong/Moderate deactivating substituents: meta substitution
○ There’s an effect of withdrawing electrons from the reactant benzene, which stabilizes the reactant.
○ For intermediates, they withdraw electrons from carbocation, making intermediates unstable
○ Reaction is slower due to higher activation energy
⑷ Most reactive group determines major product
⑸ Nucleophilic aromatic substitution (SNAr) reaction
① When leaving group (e.g., X-) and EWG are at o or p positions, a reaction occurs where nucleophile is added first, then leaving group is removed
⑹ Judgment of aromatic heterocyclic compounds
Figure 44. Dipole Moments of Aromatic Heterocyclic Compounds
② Nitration of aniline
○ For monosubstitution, meta and para substitution occur in a 1:1 ratio
○ The reason for the prevalence of meta substitution is that when the nitrogen of aniline is protonated, it acts as an electron-withdrawing group (EWG).
③ Benzofuran predominantly undergoes 2-substitution (an exception).
8. Aromatic Side Chain Effects
⑴ Summary: The adjacent carbon of phenyl (benzyl carbon) is stabilized
⑵ Specificity of addition reactions: Exception to Markovnikov’s rule
⑶ Specificity of SN2 substitution reaction
① Benzene functional groups stabilize the transition state where nucleophile approaches, increasing the rate of SN2 reaction
○ SN2 reaction rate comparison: 1° benzyl halide > 1° alkyl halide > 2° alkyl halide > 3° alkyl halide
Figure 45. Comparison of SN2 reaction rates
② The selectivity of SN2 substitution reactions.
Figure 46. The selectivity of SN2 substitution reactions by aromatic side chains in Friedel-Crafts alkylation.
⑷ Specificity of SN1 substitution reaction
① Reactant: H2O
② When carbocation is at benzyl position, resonance stabilization occurs.
③ 1° benzyl halides can undergo SN1 reaction
⑸ Specificity of E2 elimination reaction
① Reagent: NaOEt
⑹ Specificity of E1 elimination reaction
① Reagent: POCl3, pyridine
⑺ Acid-base specificity
① Acids with benzene ring that can stabilize conjugate base have high acidity
② For example, in the case of a, the acidity increases due to the stabilization of the conjugated base by the aromatic ring
Figure 47. Examples of acid base specificity
⑻ Redox reaction specificity
① Oxidation
○ Generally, oxidation of C-C bonds is not favored
○ Reagents: KMnO4, K2Cr2O7
② Reduction
○ Reagents: NaBH4, H2O
9. Synthesis Methods
⑴ Phenol synthesis
① Experimental synthesis ver. 1
○ Step 1. Benzene + HNO3 → Nitrobenzene (catalyst: sulfuric acid)
○ Step 2. Nitrobenzene + H2 / Pt → Aniline
○ Step 3. Aniline + HNO2/H2SO4 → Diazobenzene
○ Step 4. Diazobenzene + H2O → Phenol
② Experimental synthesis ver. 2
○ Step 1. Ph-NH2 + HONO → Ph-N2+
○ Step 2. Sandmeyer Reaction: Ph-N2+ + Cu2O, Cu(NO3)2, H2O
③ Industrial synthesis
○ Hydrolysis of chlorobenzene
○ Hydrolysis of benzene sulfonic acid
○ Synthesis using cumene
⑵ Kolbe-Schmitt reaction: Reaction to synthesize salicylic acid, a precursor to aspirin, a well-known antipyretic.
① Step 1. Phenol → Salicylic acid
○ Using sodium cation can allow transition state structure, selectively yielding ortho product
Figure 48. Kolbe-Schmitt reaction
② Step 2. Salicylic acid → Aspirin
○ Salicylic acid + acid anhydride → Aspirin: Recommended method
○ Salicylic acid + ester → Aspirin: Fischer Esterification
⑶ Synthesis of cresol reaction: Synthesis of cresol, used as a disinfectant, from phenol
⑷ Reimer-Tiemann reaction
① Ph-OH + 3 KOH + CHCl3 → 1-hydroxybenzaldehyde
② ortho-specific formylation of phenol forms salicylaldehyde, which is an aldehyde.
③ When strong base is treated with chloroform, the reaction occurs via the formation of dichlorocarbene: the base is the reactant.
Input: 2019.01.13 12:23
Modified: 2022.02.02 12:45