Cinnamic Acid

Supplementary information for Comprehensive Organic Chemistry Experiments for the Laboratory Classroom
© The Royal Society of Chemistry 2017

Bromination of Cinnamic acid
Supplementary Material
Experimental notes
This experiment aims at the preparation of the 2,3-dibromo-3-phenylpropanoic acid from cinnamic
acid by bromine addition.
The cinnamic acid is soluble in dichloromethane at room temperature and thus before the bromine
addition the reaction vessel holds a colourless solution. The bromine solution is intensively red-
coloured and since the addition reaction is relatively fast at this temperature, the reaction evolution
can be followed by the progressively disappearance of the red colour. The addition can be done in
30 min.
As the reaction proceeds, the product starts to precipitate and by the end of the bromine addition
there is a significant amount of the product although usually the reaction mixture is still slightly
coloured. 0.1-0.2 mL of cyclohexene are sufficient to remove all bromine traces and since the
product of this reaction, 1,2-dibromocyclohexane, is soluble in CH2Cl2 it doesn’t disturb the
isolation of the desired product. Pay attention that cyclohexene stinks with a smell that resemble
the additives present in the butane bottles which alert us to a gas leak.
The product isolation by filtration is simple and, as the dicloromethane is quite volatile, the product
can be quickly air dried and the melting point determined in the same experimental session. As the
cinnamic acid is soluble in cold CH2Cl2 the washing of the final product is essential to assure a
good purity. TLC and 1H NMR analysis confirm the purity of final product, without any cinnamic
acid contamination, and thus it is not necessary to make any recrystallization.
The measurement of the melting point allows determining the addition mode of the bromine to the
double bond. The values obtained confirm the erythro configuration of the product resulting from an
anti addition. This experiment is very reproducible and was performed with students of the first
year of the Chemistry degree. One session of 2 h is enough to perform the entire experiment which
can also be conducted in a lower scale. The yields vary between 80-93% and the melting point of
product is 206-208 ºC (lit 202-204 ºC, Mayo, D., W., Pike, R., M., Forbes, D., C. Microscale organic
laboratory: with multistep and multiscale synthesis, 5nd edition, Wiley Custom Services, chaper 7,
pp 486).
Photos of the experiment
Figure SM 4.1.1.1.1.1. The cinnamic acid solubilization in CH2Cl2
Figure SM 4.1.1.1.1.2. Reaction apparatus before the Br2 addition

Figure SM 4.1.1.1.1.3. Reaction apparatus after the Br2 addition.
a) b) c)
Figure SM 4.1.1.1.1.4. TLC plate. 60% diethyl ether/petroleum ether. a) cinnamic acid b) cinnamic
acid and product c) Product
1
H NMR and IR spectra
Figure SM 4.1.1.1.1.5. 1H NMR spectrum (400 MHz, CDCl3) of the reaction product
100
80
Transmittance (%)
60
40
20
4000 3500 3000 2500 2000 1500 1000 500

-1
W avenum ber (cm )
Figure SM 4.1.1.1.1.6. IR spectra of 2,3-dibromo-3-phenylpropanoic acid

Preparation of meso-1,2-Dibromo-1,2-diphenylethane
Experimental notes
Background topics……………………………………………………………………………………..1
Experimental details………..………………………………………………………………………….1
Figures
Photos of the experiment…………………………………………………………………….……….3
1
H-NMR spectrum…………………………………..…………………….……………………………4
Experimental notes
Background topics
This experiment illustrates a stereospecific electrophilic addition reaction to an alkene.
The experiment is appropriate to introductory/intermediate level students, who are encouraged to
rationalise the mechanism of the reaction and some experimental details through the answers to a set
of additional questions. It was already realized by over 100 students of the Faculty of Sciences and
Technology, Universidade Nova de Lisboa (in classes of 22 students/class, 11 groups of two), who
didn’t experience any difficulties.
It is important that the students understand what a stereospecific reaction is. Suggest the students to
write all the (3) stereoisomers of 1,2-dibromo-1,2-diphenylethane - the meso form and the racemic
mixture of enantiomers (and to practice drawing Fischer projections). Discuss which are optically
active. Identify enantiomers and diastereoisomers. Ask them about the results if the reaction were not
stereospecific or if the cis stereoisomer of the starting alkene were used. (If the cis isomer of the
starting material was used, the racemic mixture would be obtained).
Hints for the answers to the proposed questions and topic to discussion:
1. The crystalline perbromide is much less toxic and easier to handle than liquid bromine.
2. Stereospecificity results from the two-step mechanism explained in the Background section.
No regioselectivity is possible when two identical (C-Br) new bonds are formed.
3. There are 3 stereoisomers (the meso form, optically inactive, and the two enantiomers, each
one optically active). Optically active and inactive forms are diastereoisomers.
4. If the reaction were not stereospecific, all the isomers could be obtained, no matter which
isomer of stilbene was used as starting reagent.
Experimental details
The experiment execution is very simple, the final product is easily isolated and doesn’t need a further
purification step.
The difficulty level is low, but the hazard level is moderate to high.
Pyridine and bromine are very toxic, requiring special caution in their manipulation (see Safety
indications).
The main difficulty is drying the product; traces of acetic acid are not always easy to remove. More
than one washing with methanol may be necessary.
The product is pure white. If some red color persists, traces of bromine are still present and must be
efficiently removed (by further washing with methanol).
Some experimental results obtained by the students in the laboratory are presented in Table SM
4.1.1.2.1.
Table SM 4.1.1.2.1. Typical experimental results obtained in the Laboratory

Yield of product 70-85%
Melting point of product 236-237ºC
A very simple alternative to the experimental technique described is the direct reaction of trans-
stilbene (in acetic acid solution) with bromine (added dropwise, with caution, in a fume hood). The final
result is the same, although the use of the crystalline perbromide is less hazardous.
The preparation of samples for spectral analysis is also important.
Students should be familiarized with the technique of preparing a solid transparent disc for IR
spectroscopy, by using a small amount of a dried sample of the compound and KBr and the adequate
material. Ask them why this supporting material is adequate.
The only functional groups of the final product are the aromatic rings and the bromine atoms.
Therefore, the IR spectrum shows no very significant absorption bands. The main ones are the
following:
IR data (in KBr disc) of meso stilbene dibromide
3030-3090 cm-1: =C-H
1450 and 1500 cm-1: C=C
For 1H-NMR spectroscopy CDCl3 or DMSO-d6 are suitable solvents.
Figures
Fig. SM 4.1.1.2.1. Chemicals Fig. SM 4.1.1.2.2. Preparation of the perbromide
Fig. SM 4.1.1.2.3. Recovery of the perbromide Fig. SM 4.1.1.2.4. Addition of perbromide to stilbene
Supplementaary informatioon for Compreehensive Organ
nic Chemistry Experiments ffor the Labora
atory Classroom
m
© The Royal Society
S of Cheemistry 2017
Fig. SM 4.1.1.2.5.
4 Coo
oling the reac
ction mixture Fig. S washed final product
SM 4.1.1.2.6. Filtered and w
S
Spectra
Fig. SM 4.1..1.2.7. 1H-NM

MR spectrum
m of meso-1,2-dibromo--1,2-diphenyylethane (in C
CDCl3)
Bromination of (E)-chalcones [(E)-1,3-diarylprop-2-en-1-ones]
In this work, which is planned for a 4 hours session, students (individually or in groups of two) will
synthesize 1,3-diaryl-2,3-dibromopropan-1-one derivatives by the reaction of bromine with
(E)-chalcones. This experimental work illustrates the electrophilic addition reaction.
The desired product is obtained directly by filtration.
The bromine should be added slowly.
The 1,3-diaryl-2,3-dibromopropan-1-one derivatives are white. This experiment was performed by
nearly 50 students and the yields and melting points are an average of the students’ results.
Figure SM 4.1.1.3.1 - 1,3-diaryl-2,3-dibromopropan-1-ones structure.
Table of Results: Reaction Yield and Melting Point of some 1,3-diaryl-2,3-dibromopropan-1-ones
Entry Substituent R Substituent R1 Yield (%) Melting point (°C)

1 H H 70-80 200-202
2 H OCH3 65-75 190-192
3 OCH2C6H5 H 60-75 179-181
The most important aspects in the NMR analysis is to confirm the disappearance of the vinylic protons
and carbons of the starting (E)-chalcones and the appearance of signals due to the protons linked to a
brominated carbon atom and also the effect of the bromine in the chemical shift of the carbon atoms.
In the following figures are given, as examples, the 1H and 13
C NMR and IR spectra of 2,3-dibromo-
1,3-diphenylpropan-1-one.
Carbonyl groups are one of the most important structural units that can be revealed by IR
spectroscopy. The carbon-oxygen double bond gives a characteristic peak in the 165-1800 cm⁻1
region.
1

atory Classroom
m
Examples of IR, 1H and 13C NMR sp

pectra:
Figure SM 4.1.1.3.2 - 1H NMR spectrum (300 MHz,

M CDCl3) of the 2,3--dibromo-1,3--diphenylprop
pan-1-one
(R=R1=H).
13
Figure SM 4.1.1.3.3 - C NMR spe
ectrum (75 MHz,
M CDCl3) of the 2,3--dibromo-1,3--diphenylprop
pan-1-one
(R=R1=H).
2

atory Classroom
m
Figure SM 4..1.1.3.4 - IR spectrum

s of th
he 2,3-dibrom nylpropan-1-one (R = R1 = H).
mo-1,3-diphen
3

Preparation of trans-2-Bromocyclohexanol from Cyclohexanol

Insaturation tests (cyclohexene):

- To probe the preparation of cyclohexene, both reactions with Br2 in CCl4 and KMnO4 solutions can
be performed. In the former, the dark red solution of Br2 disappears when added to cyclohexene,
according to Scheme SM 4.1.1.4.1; the second reaction with KMnO4 solution (Baeyer test) generates
a brown precipitate (MnO2).

Br
Br2/CCl4
d
a
r
k
r
e
d
( )
Br
c
o
l
o
r
l
e
s
s
l
i
q
u
i
d
K
M
n
O
a4
q
OH
M
n
O
b
r
o
w
n
p
r
e
c
i
p
i
t
a
t
e
( )
2
OH
Scheme SM 4.1.1.4.1. Insaturation tests: Br2 in CCl4 and Baeyer test.

Infrared spectra of trans-2-bromocyclohexanol and conformational analysis:

4.0
3.5
3.0
2.5
Absorbance
2.0
1.5
1.0
0.5
0.0
-0.5
4000 3500 3000 2500 2000 1500 1000 500
-1
Wavenumber (cm )
Figure SM 4.1.1.4.1. Infrared spectrum for the neat liquid (capillary film in KBr windows). The OH
stretching band at 3400-3500 cm-1 and the lack of C=C stretching band at about 1600 cm-1 indicate
the complete conversion of cyclohexene into trans-2-bromocyclohexanol.
Peak Area Centered at (cm‐1) Width Height (Abs.)
‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐
1 13.376 3562.6 57.290 0.18629
2 165.69 3437.8 140.01 0.94427
3 130.33 3322.1 165.66 0.62770
‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐
1.4
1.2
1.0
Absorbance
0.8
0.6
0.4
0.2
0.0
3700 3600 3500 3400 3300 3200 3100

-1
Wavenumber (cm )

Figure SM 4.1.1.4.2. Expanded IR spectrum (neat liquid) in the O-H stretching region. The bands
were deconvoluted using a Lorentzian function (main results are given above). The broad bands at
3322.1 and 3437.8 cm-1 indicate intermolecular H-bonded solute molecules. The low intensity band at
higher wavenumber (3562.6 cm-1) indicates free O-H. The associated molecules are predominantly in
the diaxial conformation (60%, according to the relative band height:
[Absdiaxial/Absdiaxial+Absdiequatorial]100), because the higher intensity band centered at 3437.8 cm-1
corresponds to this conformer, according to the literature (Duarte, C. J., Freitas, M. P., "Hydrogen
bonding and stereoelectronic effects in the conformational isomerism of trans-2-bromocyclohexanol",
J. Mol. Struct., 930, 135-139, 2009).
Peak Area Centered at (cm‐1) Width Height (Abs.)
‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐
1 0.84652 3591.2 11.644 0.046281
2 6.1779 3583.2 8.6885 0.45267
‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐
0.5
0.4
Absorbance
0.3
0.2
0.1
0.0
3610 3600 3590 3580 3570 3560
-1
Wavenumber (cm )
Figure SM 4.1.1.4.3. Expanded IR spectrum (in 0.02 cyclohexane solution) in the O-H stretching
region. The bands were deconvoluted using a Lorentzian function (main results are given above). The
bands are tighter and centered at higher wavenumbers than in the neat liquid due to the lack of
intermolecular H-bond. The low intensity band at higher wavenumber (3591.2 cm-1) corresponds to
conformer diaxial, while the most intense band at 3583.2 cm-1 corresponds to the diequatorial
conformer. The conformational preferences can be estimated by comparing the relative band
intensities (9% diaxial and 91% diequatorial), and the diequatorial prevalence is due to the following
intramolecular BrHO hydrogen bond:
OH
Br
O
H
Br
Synthesis of trans-cyclohexane-1,2-diol
This experiment has been performed since the 1960s by undergraduate second-year Chemistry
students, and it is also appropriate for first year students since E1 elimination and trans-hydroxylation
are reactions taught during the first semester of Organic Chemistry. They can explore the role of acids
as catalysts in the conversion of alcohols in alkenes and realize that no nucleophilic substitution SN1
can occur because there is not a nucleophile to attack the carbocation to lead substitution. In this
experiment only one elimination product is possible. Starting from methylcyclohexanol for example,
two alkenes products (regioisomers) can be obtained. The students can also compare anti
hydroxylation with cis hydroxylation that can be accomplished using osmium tetroxide for example.
This work combines several different unit operations, such as fractional, rotary evaporator and simple
distillations, and liquid-liquid extractions. The instructor can decide to perform both steps on the
classroom or choose one of them, depending on how much time is available. Dehydration of
cyclohexanol to cyclohexane can be performed using phosphoric acid as catalyst1. Reaction scale
could be reduced for a greener process using a small vigreux column.
Additional notes on the preparation of cyclohexene:
This reaction is reversible, so to drive the reaction forward, cyclohexene is removed continuously from
the reaction mixture by fractional distillation (Figure SM 4.1.1.5.1) once it has a lower boiling point
than cyclohexanol. This step takes at least 4 hours to complete. The oil baths should be heated
initially to 160ºC and then the temperature should be lowered to 130-140ºC. The Vigreux columns
used on this experiment were 50 cm tall (about 20 inches). The distillation is complete when there is
roughly 4 mL of residue left. In the liquid-liquid extraction, the bottom layer is the aqueous. A saturated
aqueous solution of NaCl (5 mL) can be used instead solid NaCl. Cyclohexene is purified by simple
distillation; this step will be faster if an oil bath is used to heat the impure cyclohexene instead of a
water bath, despite the quite low boiling point of the product (81-83ºC2). For both distillation steps the
receiving flask must be cooled in an ice/water bath because cyclohexene is very volatile.
Figure SM 4.1.1.5.1 – Fractional distillation apparatus.
It has a characteristic gas-like odor, which may alarm the students, so if possible the distillation
should be carry out in the fume hood. According referee suggestion, this distillation can be carried out
without Vigreux column with good results.
Average yield is 40-45%. The refractive index varies between 1.4425 and 1.4538, although most
students obtained values between 1.4462 and 1.4468 (nD=1.44652).

Additional notes on the preparation of trans-cyclohexane-1,2-diol:
This step requires two sessions. Reaction apparatus for trans-cyclohexane-1,2-diol is shown in Figure
SM 4.1.1.5.2. Temperature reaction is easily controlled and the cold water bath is rarely necessary.
Cyclohexene should be added through a dropping funnel with pressure equalizer to minimize odor.
Figure SM 4.1.1.5.2 – Reaction set-up apparatus.
The peroxide test is always positive and so the reaction mixture is stirred with heating for 30 more
minutes. Even after this time, the peroxide test remains positive and FeSO4 must always be added to
the reaction mixture. The distillation of water and formic acid with a rotary evaporator ends the first
session. In the hydrolysis step warming can be extended for more than 15 min and may be followed
by tlc. On the liquid-liquid extraction the aqueous layer is also on the bottom. The filtration step was
skipped after removing the ethyl acetate on the rotary evaporator and the product was immediately
recrystallized on the same flask, minimizing any losses. Alternatively, acetone can be used for
recrystallization. Trans-cyclohexane-1,2-diol is obtained with an average yield of 35-40%. Melting
points are between 95 and 104ºC with a melting point range of 1-2ºC (lit.: 105ºC2).
IR spectra:
IR spectra of all products are available in the literature (Spectral Database for Organic Compounds,
SDBS nº 569 for cyclohexene and nº 2416 for trans-cyclohexane-1,2-diol3). It is difficult to obtain the
IR spectrum for cyclohexene due to its high volatility resulting in lower bands intensities. For that
reason C=C absorption band at 1438 cm-1 is not visible. Nevertheless students easily identify in the
Figure SM 4.1.1.5.3 a strong band at 2930 cm-1 due to the aliphatic C-H absorption and at 3020 cm-1
for =C-H absorption.
Figure SM 4.1.1.5.3: IR (liquid film) of cyclohexene
In the Figure SM 4.1.1.5.4 is visible the strong O-H absorption band at 3100-3600 cm-1.
Figure SM 4.1.1.5.4: IR (KBr) of trans-cyclohexane-1,2-diol
1
H NMR spectrum
Students easily distinguish CH2 protons from CH protons in Figure SM 4.1.1.5.5 for cyclohexene.
Figure SM 4.1.1.5.5: 1H NMR (CDCl3) of cyclohexene
The students analyzed the 1H NMR spectrum of trans-cyclohexane-1,2-diol available in literature3.
1
Fieser, L. F.; Williamson, K. L. Organic Experiments, Houghton Mifflin Company: 8th ed., 1998, 235.
2
R. Weast, CRC Handbook of Chemistry and Physics, 1st Student ed., 1988, C-230.
3
URL: http://sdbs.db.aist.go.jp/sdbs/cgi-bin/direct_frame_top.cgi, access in Sep 2015.
Synthesis of isobutylene and its use in esterification reactions

This experiment has been performed by students of the second year of the Biochemistry degree, in
the course of Organic Chemistry (introduction level). Theoretical aspects of carbocation stability,
alkene geometry, chemistry of the double bond, dehydration of alcohols and general principals of ester
formation have been covered in class by the time this experiment is introduced. In previous lab
sessions, student performed identification of alkenes by colorimetric tests based on addiction to the
double bond and the (usual) synthesis of fruit aromas by Fischer esterification with primary and
secondary alcohols, so the basic concepts have been discussed.
From the experimental point of view, the novelty is the manipulation of a reactant in the gas phase and
its use in situ.
It can be used simply to illustrate the topic of alcohol elimination, instead of the more common
cyclohexanol dehydration that requires a long, boring, reflux period (where on colorless liquid turns
into another colorless liquid), or/and to introduce the discussion of heterogeneous versus
homogeneous catalysis: it is possible to have groups using sulphuric acid as catalysts while others
use oxalic acid; the latter is easily recovered (80% or more) and ready to reuse. Other heterogeneous
catalysts can be evaluated and compared to oxalic acid.
The subsequent reaction that was chosen at this level was esterification of a carboxylic acid. Both
benzoic and cinnamic acid are good choices.
During this step, isobutylene, generated in a separate apparatus, is again protonated by H2SO4
originating the tertiary carbocation (electrophile) which is then attacked by the oxygen of the carboxylic
acid (nucleophile) in a different mechanism of the usual Fischer reaction, where the oxygen of the
alcohol is the nucleophile.
O O
+ H+
OH HO
O
Scheme SM 4.1.1.6.1. Acid-catalyzed Fischer esterification, involving primary (or secondary) alcohols.
Notice that the oxygen atom of the ester originates from the alcohol, which is the nucleophile in this
mechanism.
1

H+
O O
OH O
Scheme SM 4.1.1.6.2. Acid-catalyzed esterification, involving tertiary alcohols. Notice that the oxygen
atom of the ester originates from the carboxylic acid, which is now the nucleophile.
On the first time this experiment was performed by our students, the setup was that described by
Cunha et al. in Química Nova, 2003, 26(3) 425-427. The yields were very low (<30%) and, since then,
we introduced several modifications to the protocol, mainly by sealing the connection between the gas
producing system and the esterification vessel and keeping this at a low temperature all the time (see
photos of experiment). A rubber stopper, suitable for the Erlenmeyer were the esterification was to
occur, was bored to accommodate a glass Pasteur pipette, tightly fitting.
Some useful tips for better results:

- Use a new pipette, with a long tip and insert it the hole of the stopper while (or before) the oxalic
acid/tert-butanol is being heated. Depending on the students´ dexterity, it may be better that this
task is performed by the instructor or the lab technician to avoid nasty cuts.
- Clamp the piece by the stopper and insert the tip in a testing tube containing potassium
permanganate solution. The first bubbles are just air being pushed out of the round bottom flask;
after a few minutes, a brownish ring shows in the test tube: this is manganese oxide being formed
and indicates that the gas bubbling in the tube is now the alkene. Using sodium carbonate solution
to dissolve KMnO4 can make this color change more evident, since in alkaline medium the
manganese goes from oxidation state VII (purple) to IV (green) before forming Mn II (brown,
insoluble). Bromine in water works just as well.
- When there is a regular production of gas bubbles and the reaction vessel is ready in its ice bath,
clip the tip of the pipette so that is long enough to immerse in the reaction mixture when the
stopper is firmly sealing the Erlenmeyer. This should be tested before starting the reactions. The
stopper can be involved in parafilm. Regular stirring help gas dissolution and leads to better yields.
2

The longer the gas is allowed to bubble in the acid solution, the higher the yield will be. 2 hours will
give about 30% conversion.
- Removing the pipette for storing between lab periods can be tricky since it is usually very tight.
Taking off the stopper results in large losses of alkene; our solution was to remove the hose,
leaving the pipette and close it with a piece of rolled up parafilm. The whole ensemble goes to the
refrigerator.
- On the second session, it is important to cool down in an ice bath before opening the flask, since
pressure can build up during storage.
The ester is easily obtained by liquid-liquid extraction as described. Care must be taken during the
washing of the organic phase with sodium bicarbonate due to the presence of acid resulting in built up
pressure and foaming. Phase separation is simple, although there is the need to dry the organic phase
with Na2SO4.
The ester is obtained as a clear yellowish oil of low viscosity and good purity by removing the solvent
in the rotavapor at 50ºC (benzoic acid as impurity could be detected in the NMR spectrum). Refractive
index is 1.4900-1.4920, at 20ºC.
FTIR is a suitable technique to characterize the product, considering that its spectrum shows very
clear changes from that of the parent acid (Figures SM 4.1.1.6.5 and SM 4.1.1.6.6, for benzoic and
cinnamic products, respectively). Spectra of solid acids were obtained as KBr pellets and spectra of
esters as thin films on KBr windows.
The main features are the disappearance of the complex bands in the region 3300-2500 cm-1 due to
OH stretching and at 140 and 940 cm-1 (symmetric and asymmetric OH bending) of the acid and the
shift from 1690 to 1725 cm-1 of the C=O stretching from acid to ester.
For students with more advanced knowledge on molecular spectroscopy techniques, NMR (both 1H
and 13C) spectra can be obtained and discussed, as seen in Figures SM 4.1.1.6.7- SM 4.1.1.6.10.
When this experiment was performed by instructors, yields 60-65% were obtained. When performed
by 2nd year students, the yields dropped to 35-55%. In lab classes, students also performed the
recovery of unreacted benzoic acid and of catalyst, oxalic acid, by recrystallization.
3

Photos of experiment
Before After
Figure SM 4.1.1.6.1 – Isobutylene set up, showing test tube before and after alkene bubbling
Figure SM 4.1.1.6.2 – Benzoic acid in dichloromethane and H2SO4
4

Figure SM 4.1.1.6.3 - Esterification in progress, pipette

from isobutylene generation system inserted in acid
mixture.
Figure SM 4.1.1.6.4 – Liquid-liquid extraction of ester, showing some emulsion in the organic
phase. This clears up with the addition of sodium sulphate.
5

Figure SM 4.1.1.6.5 – FTIR spectra of benzoic acid (red) and tert-butyl benzoate (blue)
Figure SM 4.1.1.6.6 – FTIR spectra of cinnamic acid (red) and tert-butyl cinnamate (blue)
6

atory Classroom
m
Figure SM 4.1.1.6.7 – 1H NM
MR spectrum
m (400 MHz, CDCl3) of b
benzoic acid
Figure SM 4.1.1.6.8 – 1H NM
MR spectrum obtained tert-butyl benzo
m (400 MHz, CDCl3) of o oate
7

atory Classroom
m
Figure SM 4.1.1.6.9 – 13C NMR spectrum

m (400 MHzz, CDCl3) of o
obtained benzoic acid
Figure SM 4.1.1.6.10 – 13C NMR

N spectru
um (400 MH
Hz, CDCl3) off obtained te
ert-butyl ben
nzoate
8

Hydroxyl group protection via tetrahydropyranyl ether formation

Protecting groups play an important role in organic synthesis. This experiment aims the protection of
hydroxyl group by tetrahydropyranyl ether formation. Among the various methods for protecting
hydroxyl groups, the formation of tetrahydropyranyl ethers is one of the most widely used because of
their easy formation and inertness to a range of reaction conditions.
The mechanism of the tetrahydropyranyl ether formation (Scheme SM 4.1.1.7.1) is an acid-catalyzed

addition of the alcohol to the double bond of the dihydropyran. Dihydropyran is especially reactive
toward such an addition because the oxygen stabilize the carbocation that is initially produced in the
reaction. In general, almost any acidic reagent or reagent that generates an acid in situ can be used to
introduce the tetrahydropyranyl group.1, 2
p-Toluenesulfonic acid (p-TsOH), (Scheme SM 4.1.1.7.1)
and pyridinium p-toluenesulfonate (PPTS), a weakly acidic salt, are frequently used in this protection.
The reaction mechanism of these acids is comparable, both protonate the dihydropyran, however in
the PPTS case the proton comes from the pyridinium salt.
Scheme SM 4.1.1.7.1 – (a) Pyridinium p-toluenesulfonate structure. (b) Mechanism of the

tetrahydropyranyl ether formation.
Most of the reported methods for tetrahydropyranyl ether formation use acidic reagents in an aprotic
solvent, such as dichloromethane, tetrahydrofuran or toluene.1-Phenyl-cyclohexene may compete
with dihydro-4H-pyran by reacting with the protic acid such as p-toluenesulfonic acid due to the
formation of stable tertiary and benzylic carbocation. Additionally, acetic acid may compete with the
alcohol by reacting with the carbocation derived from the protonation of dihydro-4H-pyran.
Although normal ethers are difficult to cleave, a tetrahydropyranyl ether is actually an acetal, and as
such, it is cleaved under acidic conditions, such as p-toluenesulfonic acid, acetic acid, boric acid, etc.
In this line, p-toluenesulfonic acid can be used as a promoter in tetrahydropyranyl ether formation and
deprotection by using water or a simple alcohol such as methanol or ethanol as nucleophile for
transacetalization (Scheme SM 4.1.1.7.2).
Scheme SM 4.1.1.7.2. – Mechanism of tetrahydropyranyl ether deprotection.
To understand the overall process is necessary to calculate atom economy and E factor. The E-factor
is defined by the mass ratio of waste to desired product and is calculated by Equation SM 4.1.1.7.1.
total of waste (g)

E factor=
total of product (g)
Equation SM 4.1.1.7.1.
The atom economy is defined by the molecular mass ratio of desired product to all reactants and is
calculated by Equation SM 4.1.1.7.2.

x 100% Equation SM 4.1.1.7.2.

This experimental procedure has proved to be highly reproducible with yields within the 50% range.
Those results were obtained by students conducting practical organic course during two consecutive
semesters (aprox. 15 students/semester). Yields are lower than expected mainly due to losses that
occurred during the distillation process, by the used of small scale glass material available in the
teaching laboratories. The scale suggested in this work attempts to reconcile the minimization of the
use of dihydro-4H-pyran with the need to have a sufficient amount of product to perform the
distillation. The performance in a larger scale, would allow better yields.
The experimental procedure was developed in order to study the protection group concept, and the
following aspects:
1) Hydroxyl group was used as a representative example of other functional groups and also
because of its synthetic importance;
2) Tetrahydropyranyl ether formation was chosen because dihydro-4H-pyran is commercially

available at a moderate price;
3) Although methanol is a poor example of alcohol from an educational point of view, its choice is
due to the fact that other alcohols with longer chains could not be purified by distillation at
atmospheric pressure and it is necessary to use distillation under reduced pressure or a
chromatographic purification (more expensive).
In the case that these factors are not important, it will certainly be more interesting to exemplify this
transformation with other natural substrates such as menthol, geraniol or cholesterol. Moreover
geraniol and cholesterol allow further demonstration of the lack of reactivity of olefins under these
experimental conditions.
Below is provided the observed 1H NMR spectra of starting dihydro-4H-pyran (commercial sample)
and the isolated product 2-methoxyhydropyran. The students can interpret those data and explore in
more detail the conformational analysis by reading the reported literature.3 In addition, the students
can also analyze the infrared (IR) spectra of the isolated product 2-methoxyhydropyran and compare
with the commercial materials methanol and dihydro-4H-pyran and the reported IR.
___________________________
1. T. H. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1999, 49‐
54.
2. J. M. Hornback, Organic Chemistry, Cengage Learning, 2005, 1011‐1013.
3. R. J. Abraham, M. A. Warne and L. Griths, J. Chem. Soc., Perkin Trans. 2, 1998, 1751-1757.

Figure SM 4.1.1.7.1 – 1H NMR spectrum (CDCl3) of dihydro-4H-pyran commercial available.

Figure SM 4.1.1.7.2 – Expansion of 1H NMR spectrum (CDCl3) of dihydro-4H-pyran commercial

available.

Figure SM 4.1.1.7.3 – Expansion of 1H NMR spectrum (CDCl3) of dihydro-4H-pyran commercial

available.
Figure SM 4.1.1.7.4 – 1H NMR spectrum (CDCl3) of the product of methanol protection obtained after
distillation.
2-methoxytetrahydropyran IR: 2940, 1440, 1385, 1195, 1125, 1080, 1065, 1035, 955, 900, 875,
810 cm-1.4

4
P. J. Kropp, G. E. Fryxell, M. W. Tubergen, M. W. Hager, G. D. Harris, Jr., T. P. McDermott, Jr., and R. Tornero‐
Velez J. Am. Chem. Soc. 1991, 113, 7300‐7310.
Synthesis of (-)-Carvone from (+)-Limonene
Our experience shows that students tend to prefer laboratory works involving chemicals related to
real life, and specifically products that are appealing to senses, like colorants with bright collors or
fragrances. In this case, the laboratory work starts with the "citrus-smelling" (+)-limonene,
extracted before from orange oil (see experiment 1.2), and results in (-)-carvone, the essence of
spearmint. This experiment was performed for several years in our laboratory with students from
the graduation in Chemistry and Chemical Engineering.
In the first step, the conversion of limonene to limonene nitrosochloride, mechanical stirring
is more efficient than magnetic stirring, but complexity of the apparatus often limits the number
devices to be used. In the absence of 4-neck flasks, a 3-neck round-bottomed flask can be used
with a double-neck adapter. Alternatively, the second dropping funnel can be placed hanging on
top of the reflux condenser, but without obstructing its end (it is important to remind the students
that totally closed apparatus are dangerous). Average yields of limonene nitrosochloride are 20-26
g (50-56%). The product should be stored in a desiccator, and for long storage times a brown oily
product starts forming, which should not be discarded, because its probably carvoxime. Although
no further purification is needed, an analytical sample of limonene nitrosochloride may be obtained
by recrystalization from ether (mp=111-112º C)1
The final washing of carvoxime (session 2) with isopropanol was eliminated from the
original technique, since this strongly reduced the final yield of carvone. The average yield of
carvoxime is 15-17 g (80-83%). Recrystalization of the product is not necessary, since the most
probable contaminant is carvone. An analytical sample can be obtained by recrystalization from
ethanol (mp=68-72º C).1
The use of a 10 % solution of oxalic acid in the hydrolysis of carvoxime to carvone improves
the yield. Steam distillation can be stopped after collecting around 300 ml of water/carvone
mixture. From this point on the distillate contains mostly water and carvacrol, which is always a by-
product of the synthesis. Each group of students can perform the final fractional vacuum
distillation, or alternatively, after weighting and measuring the refraction index (nD= 1.4988 for pure
(-)-carvone, the average yield is 8-10 g (60-65%)), the combined products of all groups can be
distilled together. The boiling point of pure (-)-carvone at a given pressure can be obtained by the
formula log P = - 2796/Teb + 8.4782, where P is the pressure in mmHg and Teb the boiling point in
K.2 Note the use of common logarithms (base 10). The specific rotation can be measured using a
solution of 0.30 g of (-)-carvone in 50 ml of petroleum ether. The published value is []D25= -
62.46º.2 The residue of the distillation is mostly carvacrol, which can be obtained pure by
combining the residues of all the groups and collecting the fraction that distils at 120-130º C (15
mm Hg). The boiling point of carvacrol can be obtained from log P = - 3008/Teb + 8.7857.2
Carvacrol raises the refraction index of Carvone, since pure carvacrol has nD= 1.5230.2
Hints to the questions:
2) The electrophile part of the NO-Cl molecule is the NO group, and a formal addition of NO+ to the
double bond forms the most stable carbocation, i.e. the tertiary one. Addition of Cl- to the
carbocation affords the final product.
3) The endocyclic double bond is more substituted, and hence more stable.
4) The C=N double bond is conjugated with the carbon-carbon double bond, which increases the
stability of this tautomer.
5) The optical rotation is an experimental quantity, there is no relation between an enantiomer
being +/- and R/S.
Spectroscopic data:
Figure SM 4.1.1.8.1 - 1H RMN spectrum (CDCl3) of (-)-Carvone

Figure SM 4.1.1.8.2 - IV spectrum (neat) of (-)-Carvone
Figure SM 4.1.1.8.3 - 13C RMN spectrum (CDCl3) of (-)-Carvone
1
O. S. Rothenberger, S. B. Krasnof, R. B. Rollins, J. Chem. Ed., 1980, 57, 741.
2
R. Weast, CRC Handbook of Chemistry and Physics, 1st Student Ed. 1988 Florida.
Glycal transformation into surfactant 2-deoxy glycosides
Educational context……………………………………………………………………….……………………. 1
Experiment Notes…………………….…………….....………………………………………………………... 2
Preparation of dodecyl 3,4,6-tri-O-acetyl-2-deoxy-α-D-arabino-hexopyranoside………………….. 2
Preparation of dodecyl 2-deoxy-α-D-arabino-hexopyranoside...............................……...……… 5
Spectroscopic characterization of compounds………………………………………….….…..………... 7
NMR spectra ………...…………………………………………………………………………….….…………. 10
Educational context
The goal of this experiment is to demonstrate the usefulness of carbohydrate chemistry for the
generation of innovative structures with application in the medicinal chemistry field. In particular, the
relevance of 1,2-unsaturated sugars as building blocks is highlighted. The full protocol was
reproduced by 1st year Chemistry MSc students from Faculty of Sciences, University of Lisbon. The
proposed experiment, and respective discussion, was conceived for a group of students with some
theoretical background and experience working in an organic chemistry laboratory. This set of
experiments can also be applied to a small project, when extended to other fatty alcohols. The need
for a column chromatography to isolate major compounds from a reaction mixture with more than one
impurity/secondary product, some of them with very close retention factors (Rf), offers students a
valuable experience in advanced methodologies typical of a research unit daily basis.
1

Experiment Notes
 Synthesis of dodecyl 3,4,6-tri-O-acetyl-2-deoxy-α-D-arabino-hexopyranoside
Reaction of 3,4,6-tri-O-acetyl-1,5-anhydro-2-deoxy-D-arabino-hex-1-enitol with dodecanol in the
presence of TPHB reaches total completion of the starting material after 2 h, when conducted at 40
ºC. The course of the reaction can be controlled by thin layer chromatography, eluted with
cyclohexane (CyHex)/EtOAc 3:1. Although the reaction is highly stereoselective towards the dodecyl
3,4,6-tri-O-acetyl-2-deoxy-α-D-arabino-hexopyranoside (2) due to the anomeric effect, formation of the
β-anomer is also detected (Figures SM 4.1.1.9.1 and SM 4.1.1.9.2). Moreover, concomitant Ferrier
rearrangement occurs, and traces of the 2,3-unsaturated glycoside can also be detected (Figure SM
4.1.1.9.3). Glycal hydrolysis can take place under poor anhydrous conditions, detected by vestigial
TLC spots below the starting material. TLC of the glycosylation reaction is schematized in Figure SM
4.1.1.9.4.
OAc OAc OAc

O O O
AcO AcO AcO
AcO H Br AcO
AcO
-Br
OAc OAc
OAc O
AcO Br O
O AcO
AcO C12H25OH AcO AcO
AcO OC12H25 OC12H25
H
+ HBr
Figure SM 4.1.1.9.1. Mechanism of the glycosylation reaction catalyzed by acid.
Figure SM 4.1.1.9.2. Anomeric effect. The lone pair of electrons of the anomeric centre is anti-
periplanar to the C-X bond, favouring the formation of the  anomer.
2

atory Classroom
m
OAc OAc OAc

O OAc
AcO O AcO O
H Br MeCO AcO O
MeCO AcO
O
-Br
O OH
C12H25OH
OAcc
OAc
O
O
O A
AcO
HBr AcO
OC12H25
OC12H25
H
Br
Figure SM 4.1.1.9.3. Mechanism
M of
o Ferrier rea
arrangementt, catalysed by acid.
Figure SM 4.1.1.9.4 – Schematic TLC of the

e glycosylati on reaction (R) with em
mphasis on starting
material (i) and

a products
s structures (CyHex/EtO
OAc 3:1)
An efficient
e tem
mperature co
ontrol is imp
portant, as higher temp
peratures prromote both
h Ferrier
rearrangeme
ent and hydrolysis, and lower tempe
erature resu lts in longer reaction tim
mes.
omatography is the mos

Column chro st suitable method
m to iso
olate the com
mpounds illu
ustrated abo
ove. This
can be acco
omplished us
sing a colum
mn with 3 cm
m width packked with of ssilica gel 60 Å (0.040-0.6
630 mm)
up to 12 cm
m height, eluted with CyHex/EtOAc
C c 15:1 (Figu er work-up, reaction
ure SM 4.1.1.9.5). Afte
3

mixture is diluted in CyHex/EtOAc 15:1 (3 mL), with a few drops of dichloromethane (less than 1 mL),
to ensure complete dissolution. Running the column under low pressure is highly recommended. After
discharging ca. 80 mL (which will include the eluted triphenylphosphane), column fractions can be
collected in 10 mL vials. Representative TLC plates for detection of the fraction composition are
shown below (Figure SM 4.1.1.9.6).
Figure SM 4.1.1.9.5 – Column chromatography performed under external pressure applied by
compressed N2.
Figure SM 4.1.1.9.6 - Representative TLC plates of the column chromatography eluted fractions.
4

The first compound to be eluted is the Ferrier rearrangement product, the dodecyl 4,6-di-O-acetyl-
2,3-dideoxy-α-D-erythro-hex-2-enopyranoside (4), which can be isolated in yields ranging from 5-7%
(see NMR spectra in Figures SM 4.1.1.9.14 and SM 4.1.1.9.15). Although dodecanol is not shown in
Figure SM 4.1.1.9.4, it is eluted immediately after compound 4 and before the major compound,
staining pink only after prolonged heating. Dodecanol is used in this reaction in a slight excess (1.05
equiv.) to overcome further isolation challenges. Hence, the use of a higher stoichiometric ratio of
dodecanol is not recommended.
Prior to complete elution of dodecyl 3,4,6-tri-O-acetyl-2-deoxy-α-D-arabino-hexopyranoside (2),
fractions containing this compound start to be contaminated with the β-anomer 3,4,6-tri-O-acetyl-2-
deoxy-β-D-arabino-hexopyranoside (3). Students can then run the column with a more polar eluent
e.g. CyHex/EtOAc 10:1, to completely elute the α/β-anomeric mixture from the column. While the α-
glycoside is isolated with this separation process, isolation of the β-anomer would only be possible
running a second column chromatography with different eluent systems. The anomeric ratio of the
mixture can be determined from the integration of the well resolved 1H NMR signals of each anomer,
namely H-1α and H-1β (Figure SM 4.1.1.9.13). For complete NMR spectra signal assignment for both
anomers see Figures SM 4.1.1.9.9 to SM 4.1.1.9.12. Students will be able to isolate the pure α-
anomer in yields ranging from 45% to 50 %, and the anomeric mixture in yields (α/β between 3:1 and
2:1) from 25% to 30%. All compounds are isolated as colourless oils (Figure SM 4.1.1.9.7).
5

atory Classroom
m
Figure SM 4.1.1.9.7
4 – A:
A Dodecyl 4,6-di-O-acet
4 tyl-2,3-dideo
oxy-α-D-eryth
hro-hex-2-en
nopyranosid
de (4); B:
d
dodecyl 3,4,,6-tri-O-acetyl-2-deoxy-α
α-D-arabino--hexopyrano
oside (2).
 Syntthesis of dodecyl 2-deox

xy-α-D-arabiino-hexopyra
ranoside
The efficient re he O-acetyll protecting groups ca

emoval of th an be carrie
ed out by Z
Zemplén
deacetylatio
d on, a classic methodolog
gy employing
g the use off a catalytic amount of ssodium meth
hoxide in
methanol, at
a room temp
perature. Th
he NaOMe suspension
s in methanol must be fre
eshly preparred. The
d n occurs straightforwarrdly and complete conssumption off the startin

deprotection ng material can be
d
detected by
y TLC eluted
d with CyHex
x/EtOAc 1:1. The react ion can be q
quenched b
by adding accid resin,
mberlite (IR-120, H+ forrm), previou

namely Am usly washed
d with meth
hanol. Solu
ution pH sh
hould be
controlled by
b a pH tes
st paper, un
ntil complete
e neutralizattion. While neutralizing, the stir sh
hould be
g
gentle to av
void breaking
g any resin beads. Afterr filtration an duct can be isolated
nd evaporatiion, the prod
in quantitatiive yield by
y silica-gel column
c chro
omatographyy, eluted w
with ethyl accetate. Neve
ertheless
residue recrrystallization hexane 3:1 affords the

n from ethyll acetate/n-h e pure produ
uct in 85-86
6% yield
(Figure SM 4.1.1.9.8). In
I the experrimental secttion it is sug
ggested that students take the white
e solid to
a high vacuu
um line befo
ore measurin
ng the meltin
ng point, beccause time cconstrains m
make it impo
ossible to
keep it overrnight in a vacuum desiccator conta

aining desicccant and sh
hredded para
affin wax forr solvent
6

atory Classroom
m
a
adsorption. For complete NMR signal assignm
ment for com
mpound 5, ssee Figures
s SM 4.1.1.9
9.16 and
SM 4.1.1.9.1
S 17.
Figure SM 4.1.1.9.8
4 – Recrystaliza
R tion of dodecyl 2-deoxy--α-D-arabino
o-hexopyranoside (5), fro
om ethyl
aceta
ate/ n-hexane
e.
Phys
sical and sp
pectroscopiic characterrization of c
compounds
s:
Dodecyl 3,4,6-tri-O-ac
cetyl-2-deox
xy-α-D-arabiino-hexopyranoside (2
2): +66 (c 1, CH2Cl2); Rf
c/CyHex 1:3); IR (neat): 1748 cm-1 (C=O);

0.58 (EtOAc ( 1
NMR (CDCl3) δ 5.33 (ddd, 1H, J3,2a 11.9 Hz,
HN
J3,2e 5.5 Hz, J3,4 9.8 Hz,, H-3), 5.00 (t, 1H, J4,5 10.0
1 4), 4.94 (d, 1H, J1,2a 3.1 Hz, H-1), 4
Hz, H-4 4.32 (dd,
7 Hz, J6a,6b 12.3 Hz, H-6a), 4.06 (dd, 1H, J6b,5 2 .2 Hz, H-6b), 3.97 (ddd, 1H, J5,4 = 10.0 Hz,
1H, J6a,5 4.7
H-5), 3.62 (d
dt, 1H, J1’a,1’bb 9.4 Hz, J1’aa,2’ 6.2 Hz, H-1’a),
H H-1’b), 2.24 (dd, 1H,
3.38 ((dt, 1H, J1’b,22’a,b 6.2 Hz, H
J2e,2a 12.9 Hz,

H J2e,3 5.7 Hz, H-2e), 2.10
2 (s, 3H,, CH3-Ac), 2
2.05 (s, 3H, CH3-Ac), 2..02 (s, 3H, C
CH3-Ac),
1.83 (td, 1H, H-2a), 1.63 2 H- 2’a,b)), 1.37-1.22 (m, 18H, H--3’- H-11’), 0
3-1.53 (m, 2H, 0.89 (t, 3H, J12’,11’ 7.1
13
Hz, H-12’); C NMR (C
CDCl3) δ 170
0.8 (C=O), 170.2
1 (C=O)), 170.0 (C=O), 96.9 (C--1), 69.5 (C--4), 69.2
(C-3), 67.9 (C-1’),

( 67.7 (C-5),
( 62.4 (C-6),
( 35.1 (C-2), 31.9, 2
29.7, 29.6, 2
29.5, 29.4, 29.3 26.2, 22
2.7 (C-2’-
C-11’), 21.0, 20.8, 20.7 (CH3-Ac), 14.1 (C-12’). Anal. Calcd

d for C24H42O8: C, 62.86
6; H, 9.23. Fo
ound: C,
63.20; H, 9.5
6 50.
7

atory Classroom
m
Dodecyl 3,4,6-tri-O-ac
cetyl-2-deox
xy-β-D-arabiino-hexopyrranoside (3
3): -19 (c 1, CH2Cl2); Rf
c/CyHex 1:3); IR (neat): 1748 cm-1 (C=O);

0.47 (EtOAc ( 1
NMR (CDCl3) δ 5.03-4.99
HN 9 (m, 2H, H-3, H-4),
4
4.56 (dd, 1H
H, J1,2a 9.7 Hz,
H J1,2e 2.0 Hz,
H H-1), 4.3 Hz, J5,6a 5.0 Hz, H-6a), 4
30 (dd, 1H, J6a,6b 12.0 H 4.11 (dd,
1H, J6b,5 2.5 H, J1’a,1’b 9.6 Hz, J1’a,2’a,b 6

5 Hz, H-6b), 3.87 (td, 1H 6.3 Hz, H-1’’a), 3.60 (dd
dd, 1H, J4,5 = 9.4 Hz,
H-5), 3.46 (ddd,

( 1H, H--1’b), 2.32 (ddd, 1H, J2ee,3 4.4 Hz, J 2a,2e 12.4 H
Hz, H-2e), 2.10 (s, 3H, C
CH3-Ac),
2.05 (s, 3H,,CH3-Ac), 2.02 (s, 3H, CH

2 C 3-Ac), 1.7
75 (ddd, 1H,, J2a,3 10.0 H
Hz, H-2a), 1.63-1.53 (m
m, 2H, H-
2
2’a,b), 1.33--1.22 (m, 18H, H-3’a,b-H 84 (t, 3H, J1 1’,12’ 6.4 Hz, H-12’); 13C N
H-11’a,b), 0.8 NMR (CDCl3) δ 99.6
(C-1), 71.9 (C-5), 71.0 (C-3), 70.8 (C-1’), 70.0 5 (C-6), 36.3 (C-2), 31..9, 29.7, 29.6, 29.5,
0 (C-4), 62.5
2
29.4, 26.0, 22.7
2 (C-2’- C-11’),
C 20.9, 20.8 (CH3-A
Ac), 14.1 (C--12’). Anal. C
Calcd for C224H42O8: C, 6
62.86; H,
9.23. Found
d: C, 63.20; H,
H 9.40.
Dodecyl 4,6-di-O-ace
4 etyl-2,3-dide
eoxy-α-D-ery 2-enopyrano
rythro-hex-2 oside (4): +48 (c 1,
CH2Cl2); Rf 0.71 (EtOAc 3); IR (neat): 1757 cm-1 (C=O); 1H N

c/CyHex 1:3 NMR (CDCl3) δ 5.90 – 5.79 (m,
2
2H, H-2, H-3
3), 5.30 (br d, 9 Hz, H-4)), 4.95 (br s, 1H, H-1), 4.28, 4.27, 4..25, 4.24 (Pa
d 1H, J4,5= 9.7 art AX of
A m, 1H, J6a,6b = 12.1 Hz, J6a,5 = 5.3 Hz, H-6a), 4. 19, 4.16 (Pa
ABX system art B of ABX
X system, 1H
H, J5,6b =
1.8 Hz, H-6b d, 1H, H-5), 3.77 (dq, 1H

b), 4.11 (ddd H-1’a), 3.50 (dq, 1H,
H, J1’a,1’b = 9. 4 Hz, J1’a,2’a,b = 6.8 Hz, H
J1’b,2’a,b = 6.6
6 Hz, H-1’b),, 2.10 (s, 3H
H, CH3-Ac), 2.09
2 (s, 3H, CH3-Ac), 1.6
66–1.54 (m,, 2H, H-2’a,b
b), 1.35–
13
1.24 (m, 18
8H, H-3’a,b to H-11’a,b), 0.88 (t, 3H,
3 J11’,12’= 7
7.1 Hz, H-1
12’); MR (CDCl3) δ 170.7
C NM
(C=O), 170.2 (C=O), 12

28.9, 127.9 (C-2,
( C-3), 94.3
9 68.9 (C-1’), 66.8 (C-5), 65.2 (C-4), 63.0 (C-
(C-1), 6
6), 29.7 (C-2

6 2´), 31.8, 29.6, 29.6, 29.5, 29.4, 29.3 6 (C-3´-C-11’), 20.9, 20.7 (CH3-Ac), 14.1 (C-
3, 26.2, 22.6
12’). Anal. Calcd

C for C222H38O6: C, 66
6.30; H, 9.61
1. Found: C,, 66.00; H, 9
9.90.
Dodecyl 2-deoxy-α-D-a xopyranosid

arabino-hex 5 ºC (EtOAc/n-hexane)); mp by
de (5). mp 113.9-115.5
DSC 114.8 ºC; +64 (c 1, MeOH);

M Rf 0.48
0 (EtOAcc); IR (neatt): 3354 cm-1 (C-OH); 1H NMR
(CD3OD) δ 4.90 (d, 1H, J1,2a 2.8 Hz, H-1), 3.90

0-3.81 (m, 2
2H, H-3, H-6
6a), 3.75-3.6
67 (m, 2H, H
H-6b, H-
1’a), 3.55 (d
ddd, 1H, J5,4 9.2 Hz, J5,6aa 2.0 Hz, J5,66b 5.3 Hz, H- 5), 3.38 (dt, 1H, J1’b,2’a = J1’b,2’b 6.3 H
Hz, J1’b,1’a
8

9.8 Hz, H-1’b), 3.26 (t, 1H, J4,3= J4,5 =9.2 Hz, H-4), 2.07 (dd, 1H, J2e,2a 12.8 Hz, J2e,3 5.2 Hz, H-2e),
1.67–1.54 (m, 3H, H-2a, H-2’a, H-2’b), 1.45–1.26 (m, 18H, H-3’a,b-H-11’a,b), 0.93 (t, 3H, J11’,12’ 6.5
13
Hz, H-12’); C NMR (CD3OD) δ 99.4 (C-1), 74.8 (C-4), 74.2 (C-5), 70.9 (C-3), 69.1 (C-1’), 63.7 (C-6),
39.8 (C-2), 34.0, 31.7, 31.6, 31.6, 31.5, 31.4, 28.3, 24.6 (C-2’-C-11’), 15.3 (C-12’). Anal. Calcd for
C14H36O5: C, 65.03; H, 10.91. Found: C, 65.10; H, 11.20.
9

NMR Spectra
1.1.9.9 - 1H NMR spectrum of dodecyl

Figure SM 4.1 d 3,4,6-trii-O-acetyl-2-deo
oxy-α-D-arabino
o-hexopyranosid
de (2), in CDCl3. *Solvent
re
esidual peak.
10

Figure SM 4.1..1.9.10 - 13C NM

MR spectrum of dodecyl 3,4,6-tri-O-acetyl-2-de
eoxy-α-D-arabino-hexopyranosiide (2), in CDCl3. *Solvent
peak.
11

1.1.9.11 - 1H NM
Figure SM 4.1 MR spectrum of dodecyl 3,4,6-tri-O-acetyl-2-de no-hexopyranosiide (3), in
eoxy-β-D-arabin
CDCl3. *So
olvent residual peak.
12

Figure SM 4.1.1.9.12- 13C NM

MR spectrum of dodecyl 3,4,6-trri-O-acetyl-2-de
eoxy-β-D-arabino
o-hexopyranoside (3), in CDCl3. *Solvent
peak.
13

ure SM 4.1.1.9.13 – 13H NMR spectrum of glyc

Figu cosides 2 and 3 in α/β ratio of 2 .8:1, in CDCl3.*Solvent peak.
14

M 4.1.1.9.14 - 1H NMR spectrum of dodecyl 4,6-di-O-acetyl-2,,3-dideoxy-α-D- erythro-hex-2-e

Figure SM enopyranoside (4), in
CDCl
C 3.*Solvent residual
r peak. In
ntegration of sig
gnals below δ 1..7 indicates con
ntamination with
h dodecanol.
15

Figure SM 4.1.1.9.15 - 13C NMR spectrum of dodecyl 4,6-di-O-acetyl-2,3-d

dideoxy-α-D-erytthro-hex-2-enop
pyranoside (4), in CDCl3.
Solvent peak.
*S
16

Figure SM 4.1.1.9.16 - 1H NMR spectrum of dodecyl 2-deo

oxy-α-D-arabino-hexopyranosid
de (5), in MeOD.*Solvent residu
ual peak.
17

Figure SM 4.1.1.9.17 - 13C NMR spectrum of dodecyl 2-deoxy-α-

2 D-ara
abino-hexopyran
noside (5), in MeOD.*Solvent p
peak.
18

Preparation of (1R,2R,3R,5S)-(–)-isopinocampheol through a

hydroboration-oxidation reaction
Experiment Notes ………………………………………………………………………………………… 1

Preparation of (1R,2R,3R,5S)-(–)-isopinocampheol …………………………….…………….. 1
Figures ……………………………………………………………………………………………………... 2
Photos of experiment ……………………………………………………………………………… 2
1
H, 13C and COSY NMR spectra …………………………………………………………………. 5
This experiment is designed for students with previous experience in the organic chemistry lab. At
Nicolaus Copernicus University, this experiment is routinely performed by graduate students at the
laboratory of Organic Synthesis.
The main objective of this experiment is to show students the hydroboration reaction and the oxidation
of the organoborane. The second objective is to introduce students to the work under anhydrous
conditions and in an inert gas atmosphere. Another purpose is to understand the regio- and
stereoselectivity of hydroboration.
There are described two methods of carry out hydroboration step as well as oxidation step. In method
1, hydroboration of (+)--pinene followed by oxidation of the organoborane is performed on one
laboratory session (Figure SM 4.1.1.10.1-SM 4.1.1.10.3). In method 2, an intermediate dialkylborane –
diisopinocampheylborane (Ipc2BH) is crystallized, isolated, and oxidized (Figure SM 4.1.1.10.4-SM
4.1.1.10.7). Instead of (+)--pinene, (–)-isomer can also be employed. Students should measure the
optical rotation of the starting -pinene, calculate the specific rotation, and based on the highest
rotation given in the experiment description calculate the optical purity of the substrate. The optical
rotation of the product isopinocampheol should also be measured. Students will compare optical
purities of α-pinene and isopinocampheol. The can observe an increase of enantiomeric purity for
isopinocampheol obtained in Method 2.
The reaction flask, as it is written, must be dried in a flame or by using a heat-gun and cool down in the
stream of nitrogen or argon. The flask and gas-inlet adapter should be assembled while still hot.
Caution is advised when taking borane solution into the syringe.
When borane-THF complex is used for the synthesis, rather freshly purchased solution should be
used. Borane-dimethyl sulfide adduct is a very stable compound when stored under nitrogen in
refrigerator, and particularly it should be used in the synthesis of crystalline, enantiomerically enriched
Ipc2BH.
Water or methanol is added to the reaction mixture to hydrolyze any unreacted borane and Ipc2BH
Both methods of oxidation of Ipc2BH are described. A safer method utilizing sodium perborate and
standard method with 30% hydrogen peroxide and 3M of sodium hydroxide.
It is mandatory to use protective gloves when handling 30% hydrogen peroxide.
Product after reaction is essentially pure, and if only the solvents are evaporated very well,
isopinocampheol can be analyzed by 1H and 13
C NMR. Small sample of isopinocampheol can be
sublimed to measure melting point and/or optical rotation as it is shown on Figure SM 4.1.1.10.8 - SM
4.1.1.10.9.
In all syntheses following Method 1, students achieved yields in the range of 60-85%, Conducting
experiments using Method 2, yields of isopinocampheol are lower (30-55%).
Flushing the apparatus

with an inert gas
Figure SM 4.1.1.10.1 – An apparatus for Figure SM 4.1.1.10.2 – The reaction mixture

hydroboration conducted under an inert gas after addition of 3M sodium hydroxide an sodium
atmosphere perborate tetrahydrate
Figure SM 4.1.1.10.3 – Reaction mixture after 1 Figure SM 4.1.1.10.4 – Crystallization of dIpc2BH

hour of oxidation (Method 1). Separation of the in water/ice/salt bath (Method 2).
two phases after stopping the stirring.
Figure SM 4.1.1.10.6 – Dissolution of dIpc2BH

Figure SM 4.1.1.10.5 – Solid dIpc2BH after upon addition of methanol or water.
washing with hexane. This compound forms large
hard crystals.
Figure SM 4.1.1.10.7 – Dissolution of dIpc2BH

with hydrogen evolution upon addition of
methanol.
Figure SM 4.1.1.10.8 – An apparatus for the

Figure SM 4.1.1.10.9 – Pure isopinocampheol
sublimation of isopinocampheol under reduced
collected on cooling finger after sublimation.
pressure.

Figure SM 4.1.1.10.10 – 1H NMR spectrum (400 MHz, CDCl3) of the starting (+)--pinene
Figure SM 4.1.1.10.11 – 13C NMR spectrum (100 MHz, CDCl3) of the starting (+)--pinene
Figure SM 4.1.1.10.12 – 1H NMR spectrum (400 MHz, CDCl3) of the product (–)-isopinocampheol
Figure SM 4.1.1.10.13 – 13C NMR spectrum (100 MHz, CDCl3) of the product (–)-isopinocampheol
Figure SM 4.1.1.10.14 – 1H NMR spectrum (700 MHz, CDCl3) of the crude product (–)-isopinocampheol from the Method 2
2 5 6
1 4
3 OH
4 6

Figure SM 4.1.1.10.15 – 1H x 1H COSY NMR spectrum (400 MHz, CDCl3) of the product (–)-isopinocampheol (numbers refer to the
carbon atoms to which protons are attached)
Figure SM 4.1.1.10.16 – 1H x 1H COSY NMR spectrum (400 MHz, CDCl3) of the product (–)-
isopinocampheol (expanded fragment of the spectrum)

Cinnamic Acid

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Supplementary information for Comprehensive Organic Chemistry Experiments for the Laboratory Classroom

© The Royal Society of Chemistry 2017

acid by bromine addition.

product of this reaction, 1,2-dibromocyclohexane, is soluble in CH2Cl2 it doesn’t disturb the

acid contamination, and thus it is not necessary to make any recrystallization.

Photos of the experiment

Figure SM 4.1.1.1.1.1. The cinnamic acid solubilization in CH2Cl2

Figure SM 4.1.1.1.1.2. Reaction apparatus before the Br2 addition

Figure SM 4.1.1.1.1.3. Reaction apparatus after the Br2 addition.

4000 3500 3000 2500 2000 1500 1000 500

Figure SM 4.1.1.1.1.6. IR spectra of 2,3-dibromo-3-phenylpropanoic acid

Table SM 4.1.1.2.1. Typical experimental results obtained in the Laboratory

Melting point of product 236-237ºC

Fig. SM 4.1.1.2.1. Chemicals Fig. SM 4.1.1.2.2. Preparation of the perbromide

Fig. SM 4.1..1.2.7. 1H-NM

Bromination of (E)-chalcones [(E)-1,3-diarylprop-2-en-1-ones]

Figure SM 4.1.1.3.1 - 1,3-diaryl-2,3-dibromopropan-1-ones structure.

Table of Results: Reaction Yield and Melting Point of some 1,3-diaryl-2,3-dibromopropan-1-ones

Entry Substituent R Substituent R1 Yield (%) Melting point (°C)

Examples of IR, 1H and 13C NMR sp

Figure SM 4.1.1.3.2 - 1H NMR spectrum (300 MHz,

Figure SM 4..1.1.3.4 - IR spectrum

Preparation of trans-2-Bromocyclohexanol from Cyclohexanol

Insaturation tests (cyclohexene):

Scheme SM 4.1.1.4.1. Insaturation tests: Br2 in CCl4 and Baeyer test.

Infrared spectra of trans-2-bromocyclohexanol and conformational analysis:

Peak Area Centered at (cm‐1) Width Height (Abs.)

1 13.376 3562.6 57.290 0.18629

2 165.69 3437.8 140.01 0.94427

3 130.33 3322.1 165.66 0.62770

3700 3600 3500 3400 3300 3200 3100

Peak Area Centered at (cm‐1) Width Height (Abs.)

1 0.84652 3591.2 11.644 0.046281

2 6.1779 3583.2 8.6885 0.45267

could be reduced for a greener process using a small vigreux column.

Additional notes on the preparation of cyclohexene:

Figure SM 4.1.1.5.1 – Fractional distillation apparatus.

without Vigreux column with good results.

students obtained values between 1.4462 and 1.4468 (nD=1.44652).

Additional notes on the preparation of trans-cyclohexane-1,2-diol:

Figure SM 4.1.1.5.2 – Reaction set-up apparatus.

recrystallization. Trans-cyclohexane-1,2-diol is obtained with an average yield of 35-40%. Melting

for =C-H absorption.

Figure SM 4.1.1.5.3: IR (liquid film) of cyclohexene

Figure SM 4.1.1.5.4: IR (KBr) of trans-cyclohexane-1,2-diol

Figure SM 4.1.1.5.5: 1H NMR (CDCl3) of cyclohexene

The students analyzed the 1H NMR spectrum of trans-cyclohexane-1,2-diol available in literature3.

Synthesis of isobutylene and its use in esterification reactions

Some useful tips for better results:

Figure SM 4.1.1.6.2 – Benzoic acid in dichloromethane and H2SO4

Figure SM 4.1.1.6.3 - Esterification in progress, pipette

Figure SM 4.1.1.6.9 – 13C NMR spectrum

Figure SM 4.1.1.6.10 – 13C NMR

Hydroxyl group protection via tetrahydropyranyl ether formation

The mechanism of the tetrahydropyranyl ether formation (Scheme SM 4.1.1.7.1) is an acid-catalyzed

Scheme SM 4.1.1.7.1 – (a) Pyridinium p-toluenesulfonate structure. (b) Mechanism of the

Scheme SM 4.1.1.7.2. – Mechanism of tetrahydropyranyl ether deprotection.

total of waste (g)

2) Tetrahydropyranyl ether formation was chosen because dihydro-4H-pyran is commercially

Figure SM 4.1.1.7.1 – 1H NMR spectrum (CDCl3) of dihydro-4H-pyran commercial available.

Figure SM 4.1.1.7.2 – Expansion of 1H NMR spectrum (CDCl3) of dihydro-4H-pyran commercial

Figure SM 4.1.1.7.3 – Expansion of 1H NMR spectrum (CDCl3) of dihydro-4H-pyran commercial

Hints to the questions: