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Supplementary information for Comprehensive Organic Chemistry Experiments for the Laboratory Classroom © The Royal Society of Chemistry 2017
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 © The Royal Society of Chemistry 2017
leading to a better yield4 (Figure SM 11.1.1). Petroleum ether (bp 40-60ºC) 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 228ºC. The melting point
range is never higher than 1ºC (literature: 227-229ºC5).
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.
Supplementary information for Comprehensive Organic Chemistry Experiments for the Laboratory Classroom © 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 112ºC,
with a melting point range never superior to 1ºC (literature: 111-113ºC6).
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.
Supplementary information for Comprehensive Organic Chemistry Experiments for the Laboratory Classroom © The Royal Society of Chemistry 2017
40600800100012001400160018002000240028003200360040001/cm
0
20
40
60
80
100
120
%T
2991
,39
283
9,9
9
267
2,19
255
0,68
88
160
9,49
1576
,70
150
7,27
424,
33
1314
,40
36
122
7,61
1199
,64
117
3,60
112
4,42
109
1,63
101
8,34
940
,23
859
,23
766
,65
703,
97
601,
75
543,
89
472
,53
SM 11.1.3: IR (KBr) of 4-bromomethylbenzoic acid
40600800100012001400160018002000240028003200360040001/cm
10
20
30
40
50
60
70
80
90
100
110
%T
297
6,9
2
2807
,20
267
7,0
1
2557
,43
2046,
33
1966,
29
194
9,9
0
1889,
15 1795
,60
169
4,3
5
161
1,4
1
157
8,6
3
1515,
94
429
,15
1380,
94
1322
,11
1291
,25
1195,
78
1182,
28
1129
,24
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,35
1019,
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0
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,12 839,
94
788,8
3
8,94
696,2
5
649
,97
546,
78
498,5
6
434
,92
SM 11.1.4: IR (KBr) of 4-methoxymethylbenzoic acid
Supplementary information for Comprehensive Organic Chemistry Experiments for the Laboratory Classroom © The Royal Society of Chemistry 2017
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.
Supplementary information for Comprehensive Organic Chemistry Experiments for the Laboratory Classroom © The Royal Society of Chemistry 2017
1
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 (171-173ºC, Aldrich), benzopinacolone (182-184ºC, 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).
Supplementary information for Comprehensive Organic Chemistry Experiments for the Laboratory Classroom © The Royal Society of Chemistry 2017
2
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
Supplementary information for Comprehensive Organic Chemistry Experiments for the Laboratory Classroom © The Royal Society of Chemistry 2017
3
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
PhHO
HH
OH
Ph
Ph
HH
OH PhPh
H
OH
H
PhPh
H
O
H
HOPh
H
H
Ph
which would give
OPh
H
Ph H
A
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
Supplementary information for Comprehensive Organic Chemistry Experiments for the Laboratory Classroom © The Royal Society of Chemistry 2017
4
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
Ph
HOPh
OH
AcOH, cat. H2SO4 Ph
O
Ph
Thermodymanicproduct
H2SO4
PhPh
O
Kineticproduct
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.
Supplementary information for Comprehensive Organic Chemistry Experiments for the Laboratory Classroom © The Royal Society of Chemistry 2017
5
1H, 13C NMR spectra and IR spectrum of benzopinacol and benzopinacolone
Figure SM 11.2.1. 1H NMR spectrum (300 MHz, CDCl3) of benzopinacol.
0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.511.5f1 (ppm)
2.00
20.1
9
1.55
3.06
7.19
7.21
7.28
7.31
7.32
7.33
7.33
7.34
Supplementary information for Comprehensive Organic Chemistry Experiments for the Laboratory Classroom © The Royal Society of Chemistry 2017
6
Figure SM 11.2.2. 13C NMR spectrum (75 MHz, CDCl3) of benzopinacol.
0102030405060708090110130150170190210230250f1 (ppm)
Supplementary information for Comprehensive Organic Chemistry Experiments for the Laboratory Classroom © The Royal Society of Chemistry 2017
7
Figure SM 11.2.3. IR spectrum of benzopinacol.
Supplementary information for Comprehensive Organic Chemistry Experiments for the Laboratory Classroom © The Royal Society of Chemistry 2017
8
Figure SM 11.2.4. 1H NMR spectrum (300 MHz, CDCl3) of benzopinacolone.
0.51.52.53.54.55.56.57.07.58.59.510.511.512.513.5f1 (ppm)
17.9
4
2.00
1.58
2.19
7.15
7.17
7.18
7.20
7.21
7.21
7.22
7.23
7.24
7.25
7.25
7.26
7.28
7.29
7.29
7.30
7.30
7.31
7.31
7.31
7.32
7.34
7.68
7.68
7.69
7.71
7.71
Supplementary information for Comprehensive Organic Chemistry Experiments for the Laboratory Classroom © The Royal Society of Chemistry 2017
9
Figure SM 11.2.5. 13C NMR spectrum (75 MHz, CDCl3) of benzopinacolone.
0102030405060708090110130150170190210230f1 (ppm)
71.1
976
.74
77.1
677
.58
126.
8012
7.74
127.
9313
1.02
131.
1913
1.84
137.
5114
3.29
198.
98
Supplementary information for Comprehensive Organic Chemistry Experiments for the Laboratory Classroom © The Royal Society of Chemistry 2017
10
Figure SM 11.2.6. IR spectrum of benzopinacolone.
Supplementary information for Comprehensive Organic Chemistry Experiments for the Laboratory Classroom © The Royal Society of Chemistry 2017
11
References:
1M. Smith; March’s 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.
Supplementary information for Comprehensive Organic Chemistry Experiments for the Laboratory Classroom © The Royal Society of Chemistry 2017
1
Iodosulfonylation-Dehydroiodination of Styrene: Synthesis of
(E)-β-tosylstyrene
Supplementary Material1
Procedure ........................................................................................................................................... 1
Analysis of purity (GC) ..................................................................................................................... 2
FTIR ..................................................................................................................................................... 2 1H NMR ................................................................................................................................................ 3 13C 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 β-tosylstyrene from the
correspondent alkene and sodium p-toluenesulfinate followed by a β-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 β-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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Supplementary information for Comprehensive Organic Chemistry Experiments for the Laboratory Classroom © The Royal Society of Chemistry 2017
5
Conformational analysis using Newman’s Projections.
This observed relative configuration can be explained through the following conformational analysis of
the β-elimination of the intermediate β-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) with permission from J. Chem. Educ., 1995, 72 (7), pp 664–665. Copyright
(1995) American Chemical Society.
2 L. K. Liu, Y. Chi, K. Y. Jen, J. Org. Chem. 1980, 45, 406.