Draw both products that are obtained when 4-chloro2-methyltoluene is treated with sodium

When benzene is treated with I2 in the presence of CuCl2, iodination of the ring is achieved with modest yields. It is believed that CuCl2 interacts with I2 to generate I +, which is an excellent electrophile. The aromatic ring then reacts with I + in an electrophilic aromatic substitution reaction. Draw a mechanism for the reaction between benzene and I +. Make sure that your mechanism has two steps, and make sure to draw all of the resonance structures of the sigma complex. I2 CuCl2

Draw a mechanism for the following reaction. Hint: This reaction is the reverse of sulfonation, so you should read the sulfonation mechanism backward. Your mechanism should involve a sigma complex (positively charged). SO3H H Dilute H2SO4

When benzene is treated with D2SO4, a deuterium atom replaces one of the hydrogen atoms. Propose a mechanism for this reaction. Once again, make sure that your mechanism involves a sigma complex. D D2SO4

Draw a mechanism for the following reaction and make sure to draw all three resonance structures of the sigma complex: NO2 HNO3 H2SO4

Predict the expected product(s) when benzene is treated with each of the following alkyl halides in the presence of AlCl3. In each case, assume conditions have been controlled to favor monoalkylation. Cl (a) Cl (b) C

Draw a mechanism for the following reaction, which involves two consecutive Friedel-Crafts alkylations. When drawing the mechanism, do not try to draw the two alkylations as occurring simultaneously (such a mechanism would have too many curved arrows and too many simultaneous charges). First draw the steps that install one alkyl group and then draw the steps that install the second alkyl group. AlCl3 Cl C

A Friedel-Crafts alkylation is an electrophilic aromatic substitution in which the electrophile (E+) is a carbocation. In previous chapters, we have seen other methods of forming carbocations, such as protonation of an alkene using a strong acid. The resulting carbocation can also be attacked by a benzene ring, resulting in alkylation of the aromatic ring. With this in mind, draw a mechanism for the following transformation: (68%) H2SO

Identify whether each of the following compounds can be made using a direct Friedel-Crafts alkylation or whether it is necessary to perform an acylation followed by a Clemmensen reduction to avoid carbocation rearrangements: (a) (b) (c) (d)

The following compound cannot be made with either a Friedel-Crafts alkylation or acylation. Explain.

A Friedel-Crafts acylation is an electrophilic aromatic substitution in which the electrophile (E+) is an acylium ion. There are other methods of forming acylium ions, such as treatment of an anhydride with a Lewis acid. The resulting acylium ion can also be attacked by a benzene ring, resulting in acylation of the aromatic ring. With this in mind, draw a mechanism for the following transformation: R O AlCl3

Draw the two major products obtained when toluene undergoes monobromination.

When ethoxybenzene is treated with a mixture of nitric acid and sulfuric acid, two products are obtained, each of which has the molecular formula C8H9NO3. (a) Draw the structure of each product. (b) Propose a mechanism of formation for the major product.

When 1,3-dinitrobenzene is treated with nitric acid and sulfuric acid at elevated temperature, the product is 1,3,5-trinitrobenzene. Explain the regiochemical outcome of this reaction. In other words, explain why nitration takes place at the C5 position. Make sure to draw the sigma complex for each possible pathway and to compare the relative stability of each sigma complex.

Does chlorination of chlorobenzene require the use of a Lewis acid? Explain why or why not?

Predict and explain the regiochemical outcome for chlorination of bromobenzene.

For each of the following compounds, determine whether the ring is activated or deactivated, then determine the strength of activation/deactivation, and finally determine the expected directing effects. NO2 (a) O (b) Br (c) N (d) O O (e) O (f) O

The following compound has two aromatic rings. Identify which ring is expected to be more reactive toward an electrophilic aromatic substitution reaction. O O

The following compound has four aromatic rings. Rank them in terms of increasing reactivity toward electrophilic aromatic substitution. O O N

For each compound below, identify which position(s) is/are most likely to undergo an electrophilic aromatic substitution reaction. (a) O2N CH3 NO2 CH3 (b) O2N NO2 O O O O (c) CN (d) N O (e) O Br OH (f) (g) HO OMe (h) Br O O (i)

Predict the product(s) for each of the following reactions: O OH O HNO3 (a) H2SO4 ? O OMe Br (b) ? Br2 FeBr3 Br O ? (c) Fuming H2SO4

When 2,4-dibromo-3-methyltoluene is treated with bromine in the presence of iron (Fe), a compound with molecular formula C8H7Br3 is obtained. Identify the structure of this product.

For each of the following compounds, determine the position that is most likely to be the site of an electrophilic aromatic substitution reaction: (a) HO NO2 OMe Br O2N (b) (c) O (d) O HO OH (e)

The following compound is highly activated but nevertheless undergoes bromination very slowly. Explain. O O O

When the following compound is treated with Br2 in the presence of a Lewis acid, one product predominates. Determine the structure of that product. O ? Br2 FeBr3

Determine whether a blocking group is necessary to accomplish each of the following transformations: (a) NO2 (b) Br N O N O Br (c) HO HO NO2 (d)

Predict the major product of the following reaction: SO3H SO3H HO3S Dilute H2SO4 ?

The following transformations cannot be accomplished, even with the help of blocking groups. In each case, explain why a blocking group will not help. HO OH HO OH (a) NO2 Br (b)

Identify the reagents necessary to convert benzene into each of the following compounds: (a) Chlorobenzene (b) Nitrobenzene (c) Bromobenzene (d) Ethylbenzene (e) Propylbenzene (f) Isopropylbenzene (g) Aniline (aminobenzene) (h) Benzoic acid

Identify the product obtained when benzene is treated with each of the following reagents: (a) Fuming sulfuric acid (b) HNO3 /H2SO4 (c) Cl2, AlCl3 (d) Ethyl chloride, AlCl3 (e) Br2, Fe (f) HNO3 /H2SO4 followed by Zn, HCl

Starting with benzene and using any other necessary reagents of your choice, design a synthesis for each of the following compounds. Note: some of these problems have more than one plausible answer. (a) H2N Br O2N Cl (b) H2N (c) NH2 (d) Cl CBr Br 3 (e) Br CBr (f) 3 (g) (h) NO2 Cl (i) (j)

Using only reactions that we learned in this chapter, there are two different ways to prepare the following compound from benzene. Identify both ways and then determine which way is likely to produce a better yield of the desired product. Explain your choice.

The following compounds cannot be made using only reactions that we learned in this chapter. For each compound, explain the issues that prevent its formation: NO2 NH2 (a) (b)

Starting with benzene and using any other necessary reagents of your choice, design a synthesis for each of the following compounds. In some cases, there may be more than one plausible answer. O Br (a) H2N Br (b) NH2 Cl Cl (c) Br SO3H Cl

The compound below has a pentasubstituted benzene ring. (a) Starting with benzene and using any other necessary reagents of your choice, design a synthesis for this compound. (b) It is very difficult to install a sixth substituent. Explain. (c) Is the ring activated or deactivated (relative to benzene)? Justify your answer. Br Br O OH Cl C

Predict the product of the following reaction: Br Cl NO2 NaOCH3, heat

Starting with benzene and using any other necessary reagents of your choice, design a synthesis for the following compound: HO NH2

The presence of additional nitro groups can have an impact on the temperature at which a nucleophilic aromatic substitution will readily occur. Consider the following example: Cl NO2 R R OH NO2 R R 1) NaOH 2) H3O+ When both R groups are hydrogen atoms, the reaction readily occurs at 130C. When one of the R groups is a nitro group, the reaction readily occurs at 100C. When both R groups are nitro groups, the reaction readily occurs at 35C. (a) Provide an explanation that justifies the lower temperature requirement with additional nitro groups. (b) If a fourth nitro group is placed on the ring, would you expect the temperature requirement to be significantly lowered further? Explain your answer.

Draw both products that are obtained when 4-chloro2-methyltoluene is treated with sodium amide followed by treatment with H3O+.

Starting with benzene and using any other necessary reagents of your choice, design a synthesis for anisole (methoxybenzene).

Draw the most likely mechanism for each of the following transformations: Br OH 1) NaOH, 350C 2) H3O+ (a) Br Br2 FeBr3 (b) I O2N O2N (c) NH2 1) NaNH2 2) H3O

When 2-ethyl-5-chlorotoluene was treated with sodium hydroxide at high temperature, followed by treatment with H3O+, three constitutional isomers with molecular formula C9H12O were obtained. Draw all three products.

When ortho-bromonitrobenzene is treated with NaOH at elevated temperature, only one product is formed. (a) Draw the product. (b) Identify the intermediate formed en route to the product. (c) Would the reaction occur if the starting compound were meta-bromonitrobenzene? (d) Would the reaction occur if the starting compound were para-bromonitrobenzene?

Identify the reagents necessary to accomplish each of the following transformations: Br Cl NO2 SO3H O CBr3 OH O NH

Rank the following compounds in order of increasing reactivity toward electrophilic aromatic substitution: Br Br Br

Identify which of the following compounds is most activated toward electrophilic aromatic substitution. Which compound is least activated? NO Br 2 OH NO2 HO OMe

Predict the product(s) obtained when each of the following compounds is treated with a mixture of nitric acid and sulfuric acid: Br (a) (b) NO2 (c) O (d) OMe (e)

Predict the major product obtained when each of the following compounds is treated with fuming sulfuric acid: (a) Chlorobenzene (b) Phenol (c) Benzaldehyde (d) ortho-Nitrophenol (e) para-Bromotoluene (f) Benzoic acid (g) para-Ethyltoluene (h) Benzene

For each of the following groups, identify whether it is an activator or a deactivator and determine its directing effects: (a) OMe O O (b) (c) NH2 Cl (d) CCl (e) 3 (f) NO2 OH O (g) H O (h) Br (i) (j) NMe3

Predict the product(s) obtained when each of the following compounds is treated with chloromethane and aluminum trichloride. Some of the compounds might be unreactive. For those that are reactive, assume that conditions are controlled to favor monoalkylation. Cl (a) O O (b) NO2 (c) (d) I (e) (f) O O (g) O O O (h)

Predict the major product obtained when each of the following compounds is treated with bromine in the presence of iron tribromide: (a) Bromobenzene (b) Nitrobenzene (c) ortho-Xylene (d) tert-Butylbenzene (e) Benzenesulfonic acid (f) Benzoic acid (g) Benzaldehyde (h) ortho-Dibromobenzene (i) meta-Nitrotoluene (j) meta-Dibromobenzene (k) para-Dibromobenzene

When the following compound is treated with a mixture of nitric and sulfuric acid at 50C, nitration occurs to afford a compound with two nitro groups. Draw the structure of this product: O HNO3/H2SO4 ?

When benzene is treated with 2-methylpropene and sulfuric acid, the product obtained is tert-butylbenzene. Propose a mechanism for this transformation.

Draw a mechanism for each of the following transformations: Cl (a) Cl2 AlCl3 NO2 HNO3 H2SO4 (b) SO3H Fuming H2SO4 (c) (d) CH3Cl AlCl3 Br (e) Br2 Fe

Propose a plausible mechanism for each of the following transformations: I AlCl3 I Cl (a) CH2Cl2 AlCl3

Propose a plausible mechanism for the following transformation: O Cl O OMe NaCl NaOMe

Predict the product(s) of the following reactions: Br ? (a) 1) HNO3, H2SO4 2) Zn, HCl 1) AlCl3, 2) Zn(Hg), HCl, heat Cl O ? (b) 1) CH3Cl, AlCl3 2) KMnO4, NaOH, heat 3) H3O ? (c) + 1) CH3Cl, AlCl3 (d) 2) Excess NBS

Starting with benzene and using any other reagents of your choice, design a synthesis for each of the following compounds: Br (a) H2N Br (b) H2N (c)

Each of the following syntheses will not produce the desired product. In each case, identify the flaw in the synthesis. NO2 Et 1) HNO3, H2SO4 2) EtCl, AlCl3 (a) Br 1) Br2, FeBr3 Cl AlCl3 2) (b) Br O 1) Br2, FeBr3 Cl 2) O AlCl3 (c) Br 2) Br2, FeBr3 1) AlCl3, Cl (d

In each case, identify the most likely position at which monobromination would occur. O (a) N O (b) O O (c)

When para-bromotoluene is treated with sodium amide two products are obtained. Draw both products and propose a plausible mechanism for their formation.

Picric acid is a military explosive formed via the nitration of phenol under conditions that install three nitro groups. Draw the structure and provide an IUPAC name for picric acid.

Propose a plausible mechanism for the following transformation: OH OH H2SO4

Benzene was treated with isopropyl chloride in the presence of aluminum trichloride under conditions that favor dialkylation. Draw the major product expected from this reaction.

Consider the structure of nitrosobenzene: N O (a) Draw the resonance structures of the sigma complex formed when nitrosobenzene reacts with an electrophile (E+) at the ortho position. (b) Draw the resonance structures of the sigma complex formed when nitrosobenzene reacts with an electrophile (E+) at the meta position. (c) Draw the resonance structures of the sigma complex formed when nitrosobenzene reacts with an electrophile (E+) at the para position. (d) Compare the stability of the intermediates from parts ac of this problem and then predict whether the nitroso group is ortho-para directing or meta directing. (e) The nitroso group has a lone pair adjacent to the ring (suggesting that it could be an activator), yet it also has a p bond to a heteroatom in conjugation with the ring (suggesting that it could be a deactivator). Experiments reveal that this group is a deactivator. Based on this information, identify which of the following groups is expected to have properties most similar to the nitroso group and explain your choice: OH NO2 CH3 Cl

Draw all resonance structures of the sigma complex formed when toluene undergoes chlorination at the para position.

For each of the following groups of compounds, identify which compound will react most rapidly with ethyl chloride in the presence of aluminum trichloride. Explain your choice in each case and then predict the expected products of that reaction. CN Cl CH3 (a) Br OMe (b)

Compound A and compound B are both aromatic esters with molecular formula C8H8O2. When treated with bromine in the presence of iron tribromide, compound A is converted into only one product, while compound B is converted into two different monobromination products. Identify the structure of compound A and compound B.

Propose an efficient synthesis for each of the following transformations: OCH3 OCH3 Br NO2 (a) OCH3 OCH3 NO2 Br (b) (c) O OH NO2 O OH (d) NO2

Predict the product(s) for each of the following reactions: O O O Br O (a) ? Cl2 AlCl3 OCH3 HNO3 H3SO3 ? (b) Fuming (c) H2SO4 ? HO Br NO2 HNO3 H2SO

Each of the following compounds can be made with a FriedelCrafts acylation. Identify the acyl chloride and the aromatic compound you would use to produce each compound. O OCH3 O2N (a) O OCH3 H3CO (b)

Aromatic heterocycles are also capable of undergoing electrophilic aromatic substitution. For example, when furan is treated with an electrophile, an electrophilic aromatic substitution reaction occurs in which the electrophile is installed exclusively at the C2 position. Explain why this reaction occurs at the C2 position, rather than the C3 position. O E O 2 3 E

Starting with benzene and using any other reagents of your choice, design a synthesis for each of the following compounds. In some cases, there may be more than one plausible answer. OMe Br Br (a) NO2 COOH COOH NO2 (b) NH2 (c) Cl Cl Br (d) NO2 NO2 Cl O (e) COOH Cl NO2 (f) Br OEt Cl (g) NO2 O Cl NO2 (h) Br O2N (i

When benzene is treated with methyl chloride and aluminum trichloride under conditions that favor trialkylation, one major product is obtained. Draw this product and provide an IUPAC name.

Compound A has molecular formula C8H8O. An IR spectrum of compound A exhibits a signal at 1680 cm-1 . The 1 H NMR spectrum of compound A exhibits a group of signals between 7.5 and 8 ppm (with a combined integration of 5) and one upfield signal with an integration of 3. Compound A is converted into compound B under the following conditions: Compound A Compound B Zn(Hg), HCl, heat When compound B is treated with Br2 and AlBr3, two different monobromination products are obtained. Identify both of these products and predict which one will be the major product. Explain your reasoning.

Starting with benzene and using any other reagents of your choice, design a synthesis for each of the following compounds. Each compound has a Br and one other substituent that we did not learn how to install. In each case, you will need to choose one of the substituents that we learned in this chapter and then modify that substituent using reactions from previous chapters. Be careful to consider the order of events in each case. Br OH (a) (b) Br

Benzene was treated with (R)-2-chlorobutane in the presence of aluminum trichloride, and the resulting product mixture was found to be optically inactive. (a) What products are expected, assuming that conditions are chosen to favor monoalkylation? (b) Explain why the product mixture is optically inactive.

The 1 H NMR spectrum of phenol exhibits three signals in the aromatic region of the spectrum. These signals appear at 6.7, 6.8, and 7.2 ppm. Use your understanding of shielding and deshielding effects (Chapter 16) to determine which signal corresponds with the meta protons. Explain your reasoning.

When toluene is treated with a mixture of excess sulfuric acid and nitric acid at high temperature, a compound is obtained that exhibits only two signals in its 1 H NMR spectrum. One signal appears upfield and has an integration of 3. The other signal appears downfield and has an integration of 2. Identify the structure of this compound and assign an IUPAC name.

Each of the following compounds is an aromatic compound bearing a substituent that we did not discuss in this chapter. Using the principles that we discussed in this chapter, predict the major product for each of the following reactions: H2SO4 HNO3 (a) ? H2SO4 ? HNO3 O (b)

Predict the major product of the following reaction: Cl Cl ? AlCl3

Bakelite is one of the first known synthetic polymers and was used to make radio and telephone casings as well as automobile parts in the early twentieth century. Bakelite is formed by treating phenol with formaldehyde under acidic conditions. Draw a plausible mechanism for the formation of Bakelite. OH OH OH OH Bakelite H H O H2SO

Propose a plausible mechanism for the following transformation: HO HO H2SO4 +

When N,N-dimethylaniline is treated with bromine, ortho and para products are observed. Yet, when N,N-dimethylaniline is treated with a mixture of nitric and sulfuric acid, only the meta product is observed. Explain these curious results. N NO2 HNO3 H2SO4 N N Br N Br Br

The rate constants for the bromination of several disubstituted stilbenes are given in the table below (J. Org. Chem. 1973, 38, 493 499). Given that the double bond of stilbene acts as the nucleophile, provide a reasonable explanation for the trend observed among the rate constants. X Y Br2 X Y Br Br X Y k (103 l/molmin) !OMe !OMe 220 !OMe !Me 114 !OMe !Cl 45 !OMe !NO2 5.2

Aminotetralins are a class of compounds currently being studied for their promise as antidepressant drugs. The following reaction was employed during a mechanistic study associated with a synthetic route for preparing aminotetralin drugs (J. Org. Chem. 2012, 77, 55035514). Propose a plausible mechanism for this transformation. CH3 Br CH3 Br Cl O O H2C CH2 AlCl3

Consider the following reaction, in which the product results from substitution of fluorine and not from substitution of chlorine (Org. Lett. 2007, 9, 27412743): NO2 Cl F C NaC NO2 Cl C C OMe OMe + (a) Draw a mechanism for this reaction. (b) Based on the observed regiochemical outcome, identify the step of the mechanism that is rate determining. Explain your answer.

Compare the indicated bonds (a and b) in the following compound. Bond a has a bond length of 1.45 , while bond b has a bond length of 1.35 (Prog. Stereochem. 1958, 2, 125). Suggest a reason for this difference in bond length for seemingly similar bonds. I NO2 NO2 O2N

Compound 1 and compound 2 both contain tritium (T), which is an isotope of hydrogen (tritium = 3 H). Both compounds are stable upon treatment with aqueous base. However, upon prolonged treatment with aqueous acid, compounds 1 and 2 both lose tritium, to give 1,3-dimethoxybenzene and 1,3,5-trimethoxybenzene, respectively (J. Am. Chem. Soc. 1967, 89, 44184424): 1 2 T OCH3 T OCH3 H3CO H3CO OCH3 (a) Draw a mechanism showing how tritium is removed from compounds 1 and 2. (b) Use your mechanism to predict which compound (1 or 2) is expected to lose tritium at a faster rate. Justify your answer.

During a synthesis of a potential anticancer agent, 7-hydroxynitidine, the investigators treated bromide 1 with two equivalents of a strong base to form compound 2 (Org. Lett. 1999, 1, 985 988). Propose a plausible mechanism to account for the following ringforming transformation: Br R R OCH2Ph N H O O R R OCH2Ph N H O O 1 2 R = OMe 1) NaNH2 (2 equivalents) 2) H2O

In the following reaction, iodine monochloride (ICl) effectively serves as a source of an electophilic iodonium species, I + (J. Org. Chem. 2005, 70, 35113517): I ICl OMe I MeO OMe A B + (a) Propose a mechanism for the formation of each of the two products, A and B. (b) The ratio of A:B in the product mixture is found to be roughly 3:1. Explain why formation of A is favored over formation of B.

Treatment of compound 1 with benzene in triflic acid (CF3SO3H) affords ammonium ion 3 (J. Org. Chem. 1999, 64, 67026705). Triflic acid is an extremely strong acid (pKa = -14), even more acidic than sulfuric acid; under these conditions, the transformation is believed to proceed via intermediate 2, a highly electrophilic dication. Draw a complete mechanism for the conversion of 1 to 3. N O N O H H N C6H6 F3C S O O

One method for the synthesis of 9,9-spirobifluorenes (rigid compounds with application to molecular electronics and light-emitting materials) involves protonation of ketone 1 with a catalytic amount of aqueous acid. Protonation of the CRO group generates an extremely powerful electrophile that facilitates a spontaneous cyclization (Org. Lett. 2004, 6, 23812383). Propose a plausible mechanism for this transformation. Br O Br OMe OMe H3O+ Br OMe Br MeO

The following synthesis was developed in an effort to prepare an analogue of a polycyclic aromatic hydrocarbon in which one of the CRC bonds was replaced with a B!N unit (J. Am. Chem. Soc. 2011, 133, 1861418617). Such derivatives are expected to display unique optical and electrical properties and thus may be useful in the preparation of novel organic electronic materials. N 1) BuLi N BCl2 N B H 1 2 3 AlCl3 2) BCl3 (a) Propose a mechanism for the conversion of compound 1 to compound 3. (b) In compound 3, do you expect each of the six rings to be aromatic, giving one extended aromatic system for the compound? Explain your answer. (c) Analysis of the actual structure of 3 (as well as its hydrocarbon analogue) reveals that the central two rings are slightly twisted (i.e., nonplanar). Provide a rationale for this finding.