The 1 H NMR spectrum of phenol exhibits three signals in

Identify the reagents necessary to accomplish each of the following transformations: Br Cl NO2 SO3H O CBr3 OH O NH2

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 (b

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 H2SO4 ? (d

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 H2SO4

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 Br2 +

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 a b

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 OH 1 2 3 H ! ! !

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.