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Supplementary information for Comprehensive Organic Chemistry Experiments for the Laboratory Classroom

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Synthesis of 4-methoxymethylbenzoic acid

Supplementary Material

This experiment was recently introduced on the list of classroom experiments and was tested by

students of intermediate organic chemistry in which the concepts of radical halogenation and

nucleophilic substitution were taught. Experimental procedure can be easily performed by first and

second-years undergraduate students. Radical halogenation experiments are commonly avoided in a

classroom due to the use of hazardous reactants. In this experiment, N-bromosuccinimide (NBS) is

used as the bromine source for the radical halogenation, which is safer and easier to use than molecular

bromine. The product obtained in the first step (4-bromomethylbenzoic acid) is not lachrymatory, unlike

most benzyl halides. Most reactions involving NBS use carbon tetrachloride as a solvent, but in this work

chlorobenzene was used instead. 4-Bromomethylbenzoic acid can also be used to synthesize

4-vinylbenzoic acid and can be found elsewhere in this book. The second step involves a nucleophilic

substitution on a saturated carbon atom, allowing discusses the two possible mechanisms (SN1 or SN2).

Several factors point out towards a SN21,2 mechanism: the methanolic solution of KOH generates the

methoxide nucleophile3 and the substituent in the aromatic ring is an electron-withdrawing carboxylic

group4 favoring SN2 mechanism by stabilization of transition state.

Additional notes on the preparation of 4-bromomethylbenzoic acid:

Benzoyl peroxide should be added carefully through a solid addition funnel, making sure that no solid

residue adheres to the side of the flask, since this reactant is potentially explosive when heated in the

solid state. For that reason, chlorobenzene is added after benzoyl peroxide to wash down any residue

remaining on the flask sides. Reflux was performed with an oil bath instead of flame, to better reach

the boiling point of chlorobenzene and also to allow the magnetic stirring of the reaction mixture,
Supplementary information for Comprehensive Organic Chemistry Experiments for the Laboratory Classroom
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leading to a better yield4 (Figure SM 11.1.1). Petroleum ether (bp 40-60C) can be substituted by

hexane.

SM 11.1.1 Reaction set-up apparatus for 4-bromomethylbenzoic acid

The obtained product can be used on the second step as it is and no further purification is needed.

Yield varies between 50-60 % while the melting point is between 226 and 228C. The melting point

range is never higher than 1C (literature: 227-229C5).

Additional notes on the preparation of 4-methoxymethylbenzoic acid:

Methanol removal on a rotary evaporator (Figure SM 11.1.2) should be performed with gentle warming

in order to avoid bumping.


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The Royal Society of Chemistry 2017

SM 11.1.2 Rotary evaporator for methanol removal

Yield of 4-methoxymethylbenzoic acid is 50-70 %. The melting point found is between 108 and 112C,

with a melting point range never superior to 1C (literature: 111-113C6).

IR spectra:

Students easily identify a strong band due to C=O group at 1700 cm-1 for 4-bromomethylbenzoic acid.

C-Br absorption can be observed at 703 cm-1 as well two intense bands at 1289 cm-1 and 1314 cm-1

due to C-H of CH2Br group (Figure SM 11.1.3). For 4-methoxymethylbenzoic acid, the same strong

band due to C=O group at 1700 cm-1 is observed. Characteristic absorption strong band for C-O-C

bonds is observed at 1099 cm-1 (Figure SM 11.1.4). The IR spectrum for 4-bromomethylbenzoic acid

can be found in SDBS under number 111037.


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120

%T

100

80

472,53
60

1507,27

1091,63
40

1124,42

1018,34

543,89
1173,60

940,23
2672,19

2550,68

1199,64
1227,61
2839,99
2991,39

1576,70

859,23
20

766,65
1609,49

601,75
1314,40

703,97
424,33

36
0

88
4000 3600 3200 2800 2400 2000 1800 1600 1400 1200 1000 800 600 40
1/cm

SM 11.1.3: IR (KBr) of 4-bromomethylbenzoic acid

110

%T

100

90
1795,60
1966,29
1949,90

1889,15
2046,33

80

434,92
70

60

50
1515,94

40
498,56
1611,41

1195,78
1578,63

1019,31

649,97

30
788,83

696,25
2677,01

2557,43

1129,24
1182,28

839,94
941,20

862,12
1380,94

20
2807,20
2976,92

1291,25
1322,11

546,78
1694,35

1099,35
429,15

10
8,94

4000 3600 3200 2800 2400 2000 1800 1600 1400 1200 1000 800 600 40
1/cm

SM 11.1.4: IR (KBr) of 4-methoxymethylbenzoic acid


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NMR spectra:

The students analyzed the 1H NMR (CDCl3) spectrum of 4-bromomethylbenzoic acid available in The

Aldrich Library of NMR Spectra8. They easily identify the aromatic protons, the protons of CH2 group

and O-H proton. 1H NMR data for 4-methoxymethylbenzoic acid is available in literature5.

1
J. March, Advanced Organic Chemistry, John Wiley & Sons, New York, 4th ed., 1992, 306.
2
Clayden, Greeves, Warren and Wothers, Organic Chemistry, Oxford, 2001, 426.
3
A. Y. Platanov, A. V. Kurzin, A. N. Evdokimov, J. Solution Chem., 2010, 39, 335.
4
M. K. Priebat, L. Chauffe, J. Am., Chem., Soc., 1976, 41, 3914.
5
E. S. Olson, J. Chem. Educ., 1980, 57, 157.
6
D. L. Tuleen, B. A. Hess, J. Chem. Educ., 1971, 48, 476.
7
http://sdbs.db.aist.go.jp/sdbs/cgi-bin/direct_frame_top.cgi, accessed in Oct 2015.
8
C. Pouchert, The Aldrich library of NMR spectra, 2nd ed., 2, 1983, 190.
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Synthesis of benzopinacolone via benzophenone photoreduction followed


by pinacol rearrangement
Supplementary Material

This experiment allows the study of the phototransformation of benzophenone to benzopinacol and
the pinacol rearrangement. These two methodologies are easily performed, reproducible, in yields
obtained by the students above 85% for each reaction, and with melting points in the range of
literature, benzopinacol (171-173C, Aldrich), benzopinacolone (182-184C, Aldrich).a

Step 1: Synthesis of benzopinacol

The photoreduction of benzophenone to benzopinacol must be carried out in a sunny place. The
benzophenone is dissolved in isopropanol that act as solvent and reagent.b Precipitation of the
product, as a white solid is then observed.c A catalytic amount of acetic acid is added to ensure the
removal of traces of alkali, which cause decomposition of the benzopinacol into benzophenone and
benzohydrol. The phototransformation of benzophenone illustrates the photochemical characteristics
of the carbonyl group, such as the radical coupling (Scheme SM 11.2.1). The reaction mechanism,
shown in Scheme SM 11.2.1, involves the formation of a radical intermediate (diradical) by the
benzophenone, which in the presence of isopropanol forms a more stable radical intermediate that, via
radical coupling originates the benzopinacol product.

a
This experiment was performed by students of different classes (aprox. 15 students/class) of organic chemistry.
b
The benzophenone slowly dissolved in isopropanol at room temperature. Sometimes the dissolution was also
achieved by gently heating.
c
If the weather is not sunny, longer time is required (up to two weeks).

1
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Scheme SM 11.2.1. Mechanism benzophenone-benzopinacol.

To enrich the mechanism discussion, comparative experiments can be carried out using different
conditions, such as absence of sunlight, and presence of the radical inhibitor butylated hydroxytoluene
(BHT). In the first case, no reaction occurs and, in the second case, reaction inhibition occurs during
the first weeks and then the formation of a precipitate is observed, although in low quantity when
compared with the reaction without BHT.

Step 2: Pinacol rearrangement

The pinacol rearrangement mechanism, involve the protonation of one hydroxyl group, water loss and
formation of a relatively stable tertiary carbocation. A 1,2-methyl shift originate an even more stable
carbocation, since the positive charge is delocalized by heteroatom resonance. In the end
deprotonation occurs to give pinacolone. This transformation illustrates a carbocation rearrangement
that is driven by the stability of the oxygen-substituted carbocation shown as the protonated carbonyl
resonance form. It is also a demonstration of the strength of the carbon-oxygen double bond.1


The mechanism of benzopinacol to benzopinacole represented in Scheme SM 11.2.2, is similar to the
mechanism described for pinacol rearrangement, however the presence of phenyl-substituents
suggest the formation of a phenonium ion as an intermediate. The iodine is considered as a mild acid
catalyst. A catalytic amount of iodine is used for promote the hydroxyl group activation in order to
facilitate the elimination of water.2

2
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Scheme SM 11.2.2. Mechanism benzopinacol-benzopinacole.

In addition to the mechanistic discussion, the pinacol rearrangement provides the opportunity to study
the carbocation rearrangement, including the relative migratory aptitudes, the carbocation stability, the
reactivity of 1,2 diols with different substituents and the kinetics versus thermodynamic product.
Examples are shown in Schemes SM 11.2.4 and SM 11.2.5.

Scheme SM 11.2.3 shows the mechanism of exclusive transformation of 1,1-diphenylethanediol to


diphenylacetaldehyde.

Ph H H H H H
H
Ph Ph
Ph OH Ph OH Ph O
Ph H A
HO H
Ph OH
Ph H
Ph H
HO which would give Ph
Ph H
O H
B

Scheme SM 11.2.3 Mechanism of the transformation of 1,1-diphenylethanediol to


diphenylacetaldehyde.

The hydroxyl group that leaves is the one whose loss gives rise to the more stable carbocation. The
carbocation A is more stable than carbocation B, since carbocation stability is enhanced by groups in
the order aryl >alkyl >hydrogen.1

3
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In Scheme SM 11.2.4 an example of the formation of kinetic or thermodynamic product, that can be
driven by using different acidic conditions, is presented.3

H2SO4 Ph AcOH, cat. H2SO4 Ph Ph


Ph Ph
Ph O HO OH O

Kinetic Thermodymanic
product product

Scheme SM 11.2.4 Kinetic and thermodynamic product formation.

The diol reacts under kinetic conditions with cold sulphuric acid, the more stable carbocation
intermediate is formed followed by 1,2-methyl group migration to originate the kinetic product. On the
other hand, under thermodynamic conditions, a less stable carbocation is formed and 1,2-phenyl
group migrates to originate the thermodynamic product.

4
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1
H, 13C NMR spectra and IR spectrum of benzopinacol and benzopinacolone

7.34
7.33
7.33
7.32
7.31
7.28
7.21
7.19

3.06

1.55
20.19

2.00

11.5 10.5 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0
f1 (ppm)

Figure SM 11.2.1. 1H NMR spectrum (300 MHz, CDCl3) of benzopinacol.

5
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250 230 210 190 170 150 130 110 90 80 70 60 50 40 30 20 10 0


f1 (ppm)

Figure SM 11.2.2. 13C NMR spectrum (75 MHz, CDCl3) of benzopinacol.

6
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Figure SM 11.2.3. IR spectrum of benzopinacol.

7
Supplementary information for Comprehensive Organic Chemistry Experiments for the Laboratory Classroom
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7.71
7.71
7.69
7.68
7.68
7.34
7.32
7.31
7.31
7.31
7.30
7.30
7.29
7.29
7.28
7.26
7.25
7.25
7.24
7.23
7.22
7.21
7.21
7.20
7.18
7.17
7.15

2.19

1.58
17.94
2.00

13.5 12.5 11.5 10.5 9.5 8.5 7.5 7.0 6.5 5.5 4.5 3.5 2.5 1.5 0.5
f1 (ppm)

Figure SM 11.2.4. 1H NMR spectrum (300 MHz, CDCl3) of benzopinacolone.

8
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198.98

143.29
137.51
131.84
131.19
131.02
127.93
127.74
126.80

77.58
77.16
76.74
71.19
230 210 190 170 150 130 110 90 80 70 60 50 40 30 20 10 0
f1 (ppm)

Figure SM 11.2.5. 13C NMR spectrum (75 MHz, CDCl3) of benzopinacolone.

9
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Figure SM 11.2.6. IR spectrum of benzopinacolone.

10
Supplementary information for Comprehensive Organic Chemistry Experiments for the Laboratory Classroom
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References:
1
M. Smith; Marchs Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Wiley, 7th

Edition, 2013, pag. 1329-1330.


2.
G. Stavber, M. Zupanand, S. Stavber, Tetrahedron Letters, 2006, 47, 8463. Hibbert, H. J. Am.

Chem. Soc., 1915, 37, 1748. M. Jereb, D. Vrazi, M. Zupan, Tetrahedron, 2011, 67, 1355.
3
A. R. Katritzky, O. Meth-Cohn, S.M. Roberts, C. W. Rees, Comprehensive Organic Functional Group

Transformations, Pergamon, Volume 1, 1995, pag. 384-386.

11
Supplementary information for Comprehensive Organic Chemistry Experiments for the Laboratory Classroom
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Iodosulfonylation-Dehydroiodination of Styrene: Synthesis of

(E)--tosylstyrene

Supplementary Material1

Procedure ........................................................................................................................................... 1
Analysis of purity (GC) ..................................................................................................................... 2
FTIR ..................................................................................................................................................... 2
1
H NMR ................................................................................................................................................ 3
13
C NMR ............................................................................................................................................... 3
Conformational analysis ................................................................................................................... 4
References and notes........................................................................................................................ 4

Radical processes are not currently used in a demonstrating laboratory because they required
expensive devices to be performed, the toxicity of reagents and products is notable, and the risk of
explosion is high. In this experiment the radical mild preparation of -tosylstyrene from the
correspondent alkene and sodium p-toluenesulfinate followed by a -elimination is described. The
initial white suspension formed by sodium p-toluenesulfinate and styrene in methanol was turning
yellow-orange as iodine was slowly added. The reaction was turning white and a new amount of iodine
was added. This gave information about the consumption of this reagent upon addition onto styrene.
At this point, sunlight was beneficial but it was of pivotal importance that vigorous stirring is used along
the process for the improvement of the chemical yield of the first step. The radical mechanism was
emphasized in order to show the students that this methodology can be used without the presence of
expensive and sophisticated reactors or lamps. The second stage represented a -elimination of
hydrogen iodide promoted by an inexpensive base like potassium hydroxide. The final sulfone could
be purified by crystallization in warm 95% ethanol, filtered (Buchner funnel) and dried (placed in a
glass vial, under vacuum using a membrane pump at room temperature for 15 min) without any
special precaution due to its high stability. The final purity could be checked by gas chromatography.
The reproducibility of the experiment was assessed by its repetitive execution by second year
undergraduate students and also by last year graduated students (range of chemical yield 78-83%,
mp. 120-121) of the University of Alicante.

The white-colorless prisms were immediately analyzed and characterized:

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Mp.: 120-12 5% ethanol [Lit.2 mp. 12


21 C from 95 20-121 C fro
om 95% etha
anol].

Rf = 0.40 (siilica gel, hex


xane/ethyl ac
cetate: 4/1).
A
Analysis of the
t purity by
y GC (Figure
e SM.11.3.1)).

GC (Figure SM.11.3.1, HP-3390A,


H WWCOT
W column, OV-10
01 stationaryy phase)
T0 = 100 C (3 min), 15 C/min, Tf = 250 C.

Figure SM.1
11.3.1. GC chromatogra
c am.

FTIR (Figure
e SM.11.3.2
2, ATR for so C=C), 1314, 1303, 1141
olids) 3042, 1614, 973 (C 1 (SO2).
FT-IR 4100L
LE (JASCO)) using PIKE
E MIRacle AT
TR device.

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Figure SM.1
11.3.2. FTIR
R spectra.

1
H NMR (30
00 MHz, CD
DCl3) : 2.42 (s, 3H, Me)), 6.86, 7.66
6 (2 d, J = 15.5 Hz, 2H, CH=CH), 7
7.32-7.48
a 7.34, J = 8.2 Hz, 7H, Ph and 2H pTol-H)
(m with a d at p and 7.83 (d, J = 8.2 Hz, 2H,, pTol-H).
Bruker AC-3
300 by using
g CDCl3 as solvent
s and TMS
T as the internal stan
ndard.

11.3.3. 1H NMR spectra.


Figure SM.1

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13
C NMR (7
75 MHz, CD
DCl3) : 21.5
5 (Me), 127
7.5, 127.6, 1
128. 5, 129
9.0, 129.9, 1
131.0, 132.4
4, 137.7,
141.9, and 144.3
1 (ArC, and
a C=C).

11.3.4. 13C NMR


Figure SM.1 N spectra
a.

Proposed Mechanism.
M

In the first step,


s the gen
neration of tosyl
t iodide, followed byy light-promo
oted homolyytic cleavage
e, trigger
tthe radical process (firs
st step). The
e intermedia
ate -iodosu
ulfone A und e -elimination upon
dergoes the
ttreatment with sodium hydroxide
h (Figure SM.11.3.5).

h
h First step

I2 + NaTs I Ts
I

I
Ts
Ts Ts
Ph Ph Ph
H A
_
OH

Ts
Ph

S
Second step

Figure SM.1
11.3.5. Two--step radicall--eliminatio
on mechanissm.

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Conformational analysis using Newmans Projections.

This observed relative configuration can be explained through the following conformational analysis of
the -elimination of the intermediate -iodosulfone A (Figure SM.11.3.6). More stable conformer A
gives the experimentally observed relative configuration of the product.

Figure SM.11.3.6. Conformational analysis of the reaction course.

References and notes

1
Reprinted(adapted)withpermissionfromJ.Chem.Educ.,1995,72(7),pp664665.Copyright
(1995)AmericanChemicalSociety.

2
L.K.Liu,Y.Chi,K.Y.Jen,J.Org.Chem.1980,45,406.