2
1) The nitration of 1-
omo-4-chlorobenzene can be ca
ied out using a mixture of nitric and sulfuric acids.
Answer the questions associated with the procedure and use the provided spectra to analyze the products
of the reaction. (29 pts total)
Experimental Procedure: To a 250 mL round bottom flask containing a stir bar, 1-
omo-4-chlorobenzene
(3.39 g, 17.77 mmol), CH2Cl2 (~20 mL), and conc. H2SO4 (~10 mL) were added. The flask was immersed
in an ice-water bath and a mixture of conc. HNO3 (~2 mL) and conc. H2SO4 (~2 mL) was added dropwise.
The reaction mixture was warmed to room temperature and sti
ed vigorously for 60 min. The reaction
was quenched by slow addition of aq. NaOH solution (~50 mL 5.5 M) and saturated aq. NaHCO3 solution
(~10 mL). To the reaction mixture was added CH2Cl2 (~20 mL), and the organic layer washed with H2O
(~20 mL) and sat. aq. NaCl solution (~20 mL). The organic phase was sti
ed over anhydrous MgSO4, and
gravity-filtered into a round bottom flask. Solvent was removed to yield a yellow solid and after further
purification was analyzed by NMR and GC-MS.
a) The expected products of mono- and di-nitration of 1-
omo-4-chlorobenzene are depicted below.
Provide the m/z value(s) expected for the molecular ions of each product. (2 pts)
3
) Predict the chemical shifts in ppm, coupling pattern, and coupling J-value(s) in Hz for each unique 1H-
atom in the mono-nitration products of 1-
omo-4-chlorobenzene. Place your answer in the designated
location in the table below. (6 pts)
shift, coupling pattern, and J value shift, coupling pattern, and J value
Ha
Hd
H
He
Hc
Hf
4
c) The mononitration products of 1-
omo-4-chlorobenzene are obtained via two different reaction
pathways. Use the B3LYP/6-31G(d) energies of the arenium cation intermediates (kcal/mol) to
determine the relative energy of each. Complete the table below and label each transition state with a
double dagger (‡) and the energy and location of each intermediate with I or II on the potential energy
surface below. (4 pts)
arenium I arenium II
C6H4O2NClB
+ C6H4O2NClB
+
B3LYP Energy
(kcal/mol)
XXXXXXXXXXkcal/mol XXXXXXXXXXkcal/mol
Relative Energy
(kcal/mol)
Br
Br
Cl
Cl
5
d) Referencing parts a) and c) and using the GC-MS data below, identify the extent of nitration (mono, di,
tri, etc.) for major products (2 and 3). Additionally, provide the ratio of product 2 to product 3 in the
form X:1 where X co
esponds to product 2. The molecules responsible for peaks labeled 1 and 4 on
the GC-trace will be addressed later. (3 pts)
GC-MS Ratio:
6
e) The 1H-NMR spectrum (CDCl3, 400 MHz) of the crude product mixture is shown below from 7.3 to 8.05 ppm. Use the labeled mononitrated
stuctures provided to label each signal with the appropriate 1H atom in the box provided. It may be useful to make reference to your answer
to question b). (6 pts)
7
f) Use the 1H-NMR data in the previous question to calculate the ratio of 1-
omo-4-chloro-3-nitrobenzene
to 1-
omo-4-chloro-2-nitrobenzene. Express the ratio in the form X:1, where X co
esponds to the
elative amount of 1-
omo-4-chloro-2-nitrobenzene. (2 pts)
g) The two impurities (1-chloro-4-nitrobenzene and 1-
omo-2-chloro-4-nitrobenzene) visible in the GC-
MS and NMR data are shown below. This spectrum is an expansion of the data provided in part e to
8.60 ppm. Assign the 1H atoms to their co
esponding signals. One of the five signals created by these
molecules is obscured by signals from the major products. (4 pts)
8
h) These two impurities cannot be readily generated by an EAS reaction from 1-
omo-4-chlorobenzene.
Suggest possible impurities in the starting material (1-
omo-4-chlorobenzene) that could be nitrated to
give these observed impurities. (2 pts)
9
2) The Claisen-Schmidt (crossed-aldol) reaction of vanillin and acetone is ca
ied out under basic
conditions followed by acidic workup as shown below. Answer the questions associated with the
procedure and use the provided spectra to analyze the products of the reaction. (32 pts total)
Experimental Procedure: To a 5 mL round bottom flask containing a stir bar was added acetone (0.784
g, 1.00 mL, 13.4 mmol), vanillin XXXXXXXXXXg, 1.3 mmol), and aq. 10 % sodium hydroxide solution (~1 mL).
The mixture was heated at reflux for 60 min and then cooled in an ice bath. Aqueous HCl solution (~30
mL, 1.2 M) was added and the resulting tan precipitate isolated by vacuum filtration. The solid was washed
with ice-cold water (~5 mL) and air dried. The product was analyzed by NMR and IR spectroscopy and
EI-mass spectrometry.
a) Aldol reactions require the formation of a nucleophile. Provide an electron-pushing mechanism for the
formation of the nucleophile in this reaction. Include all important resonance structures of the resulting
nucleophile. (3 pts)
) Using pKa values and your answer to part a), determine whether nucleophile formation is favored under
the reaction conditions. (2 pts)
c) After formation of the nucleophile there are two potential electrophiles (vanillin and acetone) available
for aldol reaction pathways. Complete the homo-aldol condensation reaction (below) and compare it to
the crossed-aldol reaction (top of page). Explain why the crossed-aldol reaction is favored in the
eaction of vanillin and acetone above. (4 pts)
10
d) In addition to the aldol addition products, it is possible to also form the aldol condensation products
under the reaction conditions. For each set of potential products there are two possible stereoisomers.
Label the relationships between the stereoisomers in each set and state whether you expect the
stereoisomers in each set to have the same or different chemical/physical properties. (2 pts)
Stereochemical
Relationship
Chemical/
Physical
Properties
e) The outcome of this reaction could be determined by use of spectroscopy NMR or IR data. Provide an
example of how each outcome (addition or condensation) could be determined by each of the methods
listed below. (4 pts)
Addition Condensation
IR
1H-NMR
11
f) The 1H-NMR spectrum (CDCl3, 400 MHz) of the purified product is shown below. Draw the product below and assign each of the labelled
signals to the co
esponding 1H-atom(s). (4 pts)
D A B C
D A
B-C
E F
G H E F
Product
12
g) The 13C-NMR APT spectrum (CDCl3, 400 MHz) of the purified product is shown below. For each signal identify the hy
idization and
number of 1H-atoms attached to the co
esponding 13C-atom (C, CH, CH2, CH XXXXXXXXXXpts)
13
h) The GC-MS data of the purified product are provided below. Provide a valid resonance structure of the
molecular ion and one or more electron-pushing mechanisms that account for the generation of ions
with m/z values of 177 and XXXXXXXXXXpts)
14
i) The addition of HCl serves two purposes in the experimental procedure. (7 pts total)
Use a balanced chemical equation in your answer to describe how HCl impacts the pH of the
solution. (3 pts)
Provide an electron-pushing mechanism to describe the role of HCl in the formation of the observed
final product. (4 pts)
15
3) The natural aromatic compound trans-anethole is used as a flavor additive. Several synthetic routes
have been developed, but vary in their selectivity for the trans stereoisomer. Answer the questions
elow and analyze the spectra provided. (18 pts total)
Experimental procedure: The tosylated (-OTs) starting materials (310 mg, 0.97 mmol) were dissolved in
tetrahydrofuran (THF, 4 mL) in a 50 mL flask, and solid potassium tert-butoxide (112 mg, 1.0 mmol) was
added. The reaction mixture was sti
ed for 30 min at room temperature followed by addition of water (3
mL) and extraction with hexanes (5 × 1 mL). The solvent was removed from the organic solution and the
esidue analyzed by 1H-NMR spectroscopy and GC-mass spectrometry.
a) Following the 30 min. reaction time, the reaction mixture undergoes extraction with water and hexane.
Label the solvent layers and the expected locations of excess potassium tert-butoxide and the product
anetholes in the resulting biphasic mixture. (2 pts)
) Compare the relative energies/stabilities of the two isomeric anethole products. Explain the source of
any energetic differences between the two products. No calculation is required in this question. (3 pts)
Top Layer
Bottom Laye
16
c) The 1H-NMR (CDCl3, 400 MHz) spectrum of the purified major product is provided below. Draw the structure of the major product in the
ox provided and assign each signal to its co
esponding 1H-atom. (6 pts)
D
A B C E
Major Product
A B
F
D C
17
d) Using the HSQC spectrum of the purified major product provided below, assign each 13C-NMR signal to its co
esponding 13C-atom in the
ox provided on the spectrum. (5 pts)
1
5
2 3
6
7
8
D A B C E F
Major Product
4
18
e) The IR spectrum of the purified major product is provided. Assign a specific functional group to any important signals > 1500 cm-1 directly
onto the spectrum. (2 pts)
19
4) Suzuki-Miyaura reactions are effective methods for coupling two sp2-hy
idized ca
on atoms together
via a palladium-catalyzed process. Answer the following questions about the coupling of 3-
furanylboronic acid and 1-
omo-4-nitrobenzene. (21 pts total)
a) Furan and its derivatives are heteroaromatic compounds that follow Hückel’s rule for aromatic
systems. Identify the approximate hy
idization of each O-atom lone pair and the O-atom in furan. (3
pts)
Approximate O-atom lone
pair hy
idization = _____
Approximate O-atom lone
pair hy
idization = _____
Approximate O-atom
hy
idization = _____
20
) State how the rate of insertion of Pd into the C-X bond of the 1-halo-4-nitrobenzene substrate to form
the co
esponding oxidative addition product would change if 1-chloro-4-nitrobenzene or