Lab Documentation—Notes to Instructors—1

Notes to instructors

Rapid and Stereoselective Conversion of a trans-Cinnamic Acid to a β-Bromostyrene

Thomas A. Evans, Department of Chemistry and Biochemistry, Ebaugh Laboratories,

Denison University, Granville, OH 43023

Email: evans@denison.edu Phone: 740-587-6496 FAX: 740-587-6673

Hazards

Gloves should be worn throughout this experiment. Dichloromethane (DCM) may be

harmful if absorbed through the skin, inhaled or ingested. Minimize contact with the liquid and
do not breathe its vapors. Prolonged exposure to DCM vapors may cause cancer or exacerbate
cardiac disease. N-bromosuccinimide (NBS) is moisture sensitive and corrosive. Inhalation of
TLC grade silica gel must be avoided. Columns of TLC grade silica gel must be prepared in a
hood. Initial elution with hexane, and preferably the entire chromatographic separation, should
be performed in a hood. Hands must be washed after handling silica gel. Dispose of the silica
gel appropriately. The use of NBS eliminates student use of bromine. β-Bromostyrene is a
volatile liquid with a characteristic odor (fragrance) that is much more easily inhaled or absorbed
through the skin than the solid β-bromo-4-methoxystyrene formed in this experiment.

Laboratory Chemical Safety Summaries (LCSS) for bromine and dichloromethane can be
accessed through a laboratory safety website maintained by the Howard Hughes Medical
Institute: http://www.hhmi.org/research/labsafe/ (accessed March 2005). These summaries were
initially developed by the National Academy of Science.

Materials and methods

All reagents were used as received. NBS, trans-4-methoxycinnamic acid and TLC grade
silica gel without fluorescent indicator or binder were obtained from Aldrich. Triethylamine was
obtained from Fisher. TLC analyses were performed using 2.5 cm x 7.5 cm plastic sheets coated
with 0.2 mm silica gel 60 with fluorescent indicator (Macherey-Nagel) and visualized under a
UV (shortwave) lamp.

NMR analysis was performed on a Bruker Avance 400 MHz instrument using CDCl3 as
solvent and TMS as the internal standard. GC analysis was performed on a 30m capillary
column operated isothermally at 140°C using an Agilent 6850 gas chromatograph equipped with
TCD (HP-1 column, Agilent No. 19091Z-431) or MSD (HP-5ms column, Agilent No. 190915-
433Z, Agilent 5973 MSD equipped with the NIST98 database of mass spectra).
 Lab Documentation—Notes to Instructors—2

Chemical reagents and consumables required for ten students.

trans-4-methoxycinnamic acid 1.8 g

N-bromosuccinimide 2.2 g
triethylamine 100 µL

dichloromethane 200 mL
hexane 200 mL
TLC grade silica gel 40 g
without fluorescent indicator
TLC slides 10-30
sodium sulfate, anhydrous 20 g

Equipment and apparatus required for each student

5 mL conical reaction vial or comparable reaction vessel

magnetic stir bar and magnetic stirrer
15 mL medium porosity fritted glass filter
10 or 25 mL Erlenmeyer flask
small test tube

Performing the experiment

There are useful visual cues for following the reaction, CO2 bubbles and the
disappearance of reactants that are initially present as suspended solids. A procedure for using
dry column vacuum chromatography to isolate the product is described. Merck silica gel (40-63
µm) can be used as an alternative to TLC grade silica gel (1). Any convenient chromatographic
method should work since the separation is not difficult. The dichloromethane used in
chromatography is removed under a stream of air in the procedure provided in the
Supplementary Materials. Use of a rotary evaporator also works very well. Chromatography
can be avoided by washing the reaction mixture with 10% NaHCO3 to remove succinimide and
residual reactants but the product may not be as pure. The procedure described provides
adequate material (ca. 125 mg, 60% yield) for analysis.

Analytical results

NMR. The aryl and vinyl regions of the NMR spectrum of the product, E-β-bromo-4-
methoxystyrene, in CDCl3 are shown in Fig. 1. Coupling constants, chemical shifts and
integration values clearly differentiate the vinyl and aryl signals. The vinyl coupling constant, J
= 13.9 Hz, establishes the E stereochemistry. The tiny doublet at δ 6.4 is evidence of a trace of
Z-isomer.
 Lab Documentation—Notes to Instructors—3

Ha H!

Hb Br

Me H"
O Ha'

Hb'

E-"-bromo-4-methoxystyrene

# 6.61 (H!, d, J = 13.9 Hz), # 6.85 (Hb, Hb')

# 7.04 (H", d, J = 13.9 Hz), # 7.23 (Ha, Ha')

! !
! !
Ha,a' H" Hb,b' H!
7.5 7.0 6.5 6.0 5.5 PPM

Figure 1. Portion of the 400 MHz NMR spectrum of E-β-bromo-4-methoxystyrene in CDCl3.

We tentatively assign the signals marked as α to the aryl and vinyl hydrogens of α-
bromo-4-methoxystyrene based on their similarity to literature reports of the NMR spectrum of
α-bromo-4-methoxystyrene (2). The presence of this material in the product of the NBS reaction
has not been reported but similar peaks are found in the NMR spectrum of E-β-bromo-4-
methoxystyrene synthesized by the Roy group (3). A mechanism to account for the formation of
the α-bromo-4-methoxystyrene is proposed below. If the less stable carbocation forms after Br+
addition, elimination of CO2 requires a hydride shift which also creates a more stable benzylic
carbocation. We have not tried to confirm the presence of the α-bromo regioisomer by
comparison with authentic material. The emphasis placed on the presence of the α-bromo
isomer and the proposed side reaction will depend upon the instructor’s goals for the experiment.

Br H COO Br H

H Br - CO2
PhCH CHCOO C C
Br COO Ph H
Ph H Ph H
!-bromostyrene
 Lab Documentation—Notes to Instructors—4

GC/MSD. Sample: dry dichloromethane solution of the reaction product after chromatography,
helium 4 mL/min (constant flow), 30m HP-5ms capillary column at 140°C; α-bromo-4-
methoxystyrene, 4.49 minutes; E-β-bromo-4-methoxystyrene, 4.84 minutes. Mass spectra of the
material represented by the two peaks are the same. Br-containing fragments are observed at M
(base peak, 212,214); M-CH3 (197, 199); and M-CH3, -CO, (169, 171). The M = 169,171 peaks
arise from fragmentation characteristic of methoxyaryl structures, e.g. anisole in the NIST98
database, as shown below(4). The M-Br peak at m/z = 133 is due to the vinyl cation formed by
loss of Br. The mass spectra of the E and Z-isomers of β-bromostyrene are reported in the
NIST98 database along with the mass spectrum of α-bromostyrene. All three spectra are
essentially the same.

H H H H H

H Br Br Br
H
- CH3 - CO
Me H H H
O H O H
H H

GC. Sample: dry dichloromethane solution of the product after chromatography, helium 25 psi
(constant pressure), 30m HP-1 capillary column; α-bromo-4-methoxystyrene (1%), 2.75
minutes; E-β-bromo-4-methoxystyrene (99%), 3.09 minutes.

Discussion

This experiment efficiently includes several important laboratory methods and analytical
techniques in the context of important reactivity, stereochemical and mechanistic principles
encountered in an introductory organic chemistry course. Although procedures for analysis by
NMR, TLC, GC and GC/MSD are described, only NMR is required.

The mechanism proposed for β-bromostyrene formation (Scheme I) draws upon

fundamental principles relevant to introductory students. By proposing formation of the open
carbocation we identify the elimination reaction as typical; in the transition state the empty and
filled orbitals that form the double bond are in the same plane. The energy difference between
the two carbocation conformers is enhanced by the coplanarity of the α-carbon and benzene ring.
In the transition state for elimination, six atoms occupy a nearly planar “ring” as shown below.
The steric interactions between bromine and the ortho hydrogen in the less stable conformer are
absent in the more stable conformer.
 Lab Documentation—Notes to Instructors—5

CO2
H

H
Br less stable
H
MeO

CO2
H

Br more stable
H
H
MeO

The role of the methoxy group in stabilizing the open carbocation can be presented as
consistent with its ability to stabilize charge when the methoxy is bonded directly to the positive
center. Just as CO2 elimination anticipates the decarboxylation reactions that students will see,
recognition of the role of the methoxy group anticipates the important role of oxygen stabilized
carbocations, for example in acetal chemistry.

NMR analysis of β-bromo-4-methoxystyrene is straightforward. Interpretation of the

mass spectrum is best accomplished by comparison with the mass spectra of anisole and β-
bromostyrene that can be found in the NIST Chemistry WebBook
(http://webbook.nist.gov/chemistry/, accessed April, 2006) and other databases (NIST98, SDBS,
(http://www.aist.go.jp/RIODB/SDBS/menu-e.html, accessed April, 2006)). The mass spectrum
for β-bromo-4-methoxystyrene is not in the NIST98 database.
 Lab Documentation—Notes to Instructors—6

Product formation
Ph = MeO

PhCH CHCOOH
O
trans-cinnamic acid

NHS Abbreviations NBS = N Br

O
Et3N
NS
NHS = N H

O
NBS NS
Et3NH Br
Br
PhCH CHCOO - CO2
PhHC CHCOO PhHC CHCOO PhCH CHBr
!-bromostyrene

Establishing stereochemistry

more stable conformer

Br
- CO2
Br H H
E-isomer
Ph
PhHC CHCOO
C O

cw rotation O
Br
Br H
PhHC CHCOO Ph COO
H
ccw rotation O

C O

H - CO2
Z-isomer
Ph H
Br

less stable conformer

Scheme I. Preferential formation of the E isomer can be accounted for by formation of the more
stable reactive conformer.

The work of Professor Roy’s group is published in journals available in electronic form
and can be easily accessed by students. This primary literature can be integral to student
experience with this experiment. It is important to note that in the experimental procedures of
the Roy articles, reaction mixtures described as 1 mM should be interpreted not as a 1 millimolar
solution but rather that 1 mmol of substance is present.
 Lab Documentation—Notes to Instructors—7

The NBS results of Professor Roy’s group suggest several alternative experiments:

1. Individualized assignments. Conversion of a variety of substituted cinnamic acids is

reported, introducing the possibility of synthesizing a variety of β-bromostyrenes (5). We have
used NBS to synthesize β-bromostyrene but prefer β-bromo-4-methoxystyrene as a more
interesting product which is easier and safer to handle.

2. Kinetics of the reaction. The reaction to form β-bromo-4-methoxystyrene, followed

spectrophotometically in the UV region, proceeds at a rate suitable for a kinetic study in the
undergraduate laboratory (5).

3. Stereochemistry of lactone formation. A γ-bromolactone is formed stereospecifically

when NBS is reacted with trans-4-phenyl-3-butenoic acid in the absence of base, as described in
the equation below (6). Reaction stereochemistry is consistent with a concerted, stereospecific
reaction involving nucleophilic participation by the carboxylic acid group, an interesting contrast
to the mechanism for formation of the vinyl bromide. The NMR spectrum of the trans lactone
and its ORTEP structure based on X-ray crystallography are included in the supplementary
material of the Roy article. However, there is no discussion of the stereochemistry of the lactone
or its mechanistic implications. Note that the alkene carboxylic acid is named incorrectly in the
article and its structure is drawn incorrectly on the NMR spectrum of the lactone included in the
supplementary material. Because all the interesting questions are not discussed in the relevant
literature, bromolactone formation might be an ideal inquiry-based project.

H H
Ph
COOH
NBS
CH3CN/H2O, RT O O
H Br
H

4. Energy differences in the conformers of the carboxylate carbocation.

Computational chemistry methods can be used to study the rotational barriers in the
carboxylate carbocation and the relative stability of its conformers. A reviewer suggested
this potential student inquiry.

Materials [CAS Reg. No]

N-bromosuccinimide [128-08-05], chloroform-d [865-49-6], dichloromethane [75-09-2], hexane

[110-54-3], trans-4-methoxycinnamic acid [830-09-1], silica gel [112926-00-8], triethylamine
[121-44-8]
 Lab Documentation—Notes to Instructors—8

Answers to questions in the Student Instructions.

1. The β-bromostyrene product is much more soluble in dichloromethane than the trans-
cinnamic acid from which it was formed. Why? How is this behavior related to the TLC results
you observed?

Relative polarity accounts for the both the difference in solubility behavior and TLC Rf values.
The less polar bromostyrene is more soluble in dichloromethane and has a much higher Rf value.

2. Carbocation conformers I and II may form in your reaction. Which is more stable? Why? Is
this important in the formation of your product?

O O

C O C O
H Ph

Ph H
H II H
I Br Br

Conformer II is more stable because there is no steric interaction between phenyl and bromine
substituents. Loss of CO2 from conformer II leads to the E isomer, which is the geometry of the
product.

3. Variously substituted trans-cinnamic acids can be reacted with NBS. Predict the relative
rates of reaction for the three compounds shown below.

O O O

OH O OH OH

O2N I H 3C N II H III
H

The predicted relative rates are I < III < II, based on the ability of the substituent to stabilize a
carbocation.
 Lab Documentation—Notes to Instructors—9

4. Use your mechanism to account for the results in related reactions as reported in the literature.

The mechanism for the first reaction is exactly like the mechanism for β-bromostyrene formation.
In the second reaction decarboxylation is not possible. The carbocation reacts with an oxygen
nucleophile. The results are consistent with either a cyclic promonium ion or an open benzylic
carbocation.

COOH Br
NBS
CO2
Et3N

C O
H

PhHC Br
H H

H H
Ph
COOH
NBS
CH3CN/H2O, RT O O
H Br
H
Br+

OH OH2

CH2
Ph
H
H
Br

5. The two-step synthesis represented below, in which the second step is microwave-
assisted, has been reported to produce Z-β-bromostyrenes. Propose a mechanism for
each step.

Anti-addition of Br2 followed by E2 elimination (anti-periplanar stereochemistry).

Br
H COOH Br2 H COOH
Ph H CHCl3
Ph H
Br

COOH
H Ph Et3N, DMF H H
mw, 1 min Ph Br
H Br
Br
 Lab Documentation—Notes to Instructors—10

Literature cited.

1. Pedersen, D.S; Rosenbohm, C. Synthesis, 2001, 2431-2434.

2. Rappoport, Z.; Apeloig, Y. J. Amer. Chem.. Soc. 1974, 96, 6428-6436; Rappoport, Z.;

Gal, A. J. Chem. Soc. Perkin Trans. 2, 1973, 301-310.

3. Supplementary material, Chowdhury, S.; Roy, S J. Org. Chem. 1997, 62, 199-200.

4. NIST/EPA/NIH Mass Spectral Library with Search Program: (Current Data Version:

NIST '02, Software Version 2.0, Standard Reference Data Program, National

Institute of Standards and Technology, 100 Bureau Dr., Stop 2310

Gaithersburg, MD 20899-2310; Kemp, W.; “Organic Spectroscopy”, 3rd Edition,

W. H. Freeman:New York, 1991, p 319.

5. Das, J. P.; Roy, S. J. Org. Chem. 2002, 67, 7861-7864 and references therein.

6. Chowdhury, S.; Roy, S. J. Org. Chem. 1997, 62, 199-200.

 Lab Documentation—Instructions Students—1

Synthesis of a β-Bromostyrene

Vinyl halides, like Z-β-bromostyrene below, can be important for their ability to
form new carbon-carbon bonds that retain the stereochemistry of the vinyl halide. In the
example below, the Z and E stereochemistry of the alkene reactants is retained in the
diene product of a palladium-catalyzed cross-coupling reaction. Such reactions are useful
only if we can obtain the alkene starting materials with the appropriate geometry.

H
H H Ph the new bond
O PdCl2(PPh3)2
H
O NaOEt
Ph Br B H H
Z
C 4H 9
H C4H9 (1Z, 3E)-1-phenyl-1,3-octadiene
E
You will perform a recently reported synthesis that transforms a trans-cinnamic
acid to a β-bromostyrene in single step, using N-bromosuccinimide (NBS) as the source
of bromine. The equation below, in which the E isomer is shown as the product, describes
the reaction. From the stereochemistry of the product, determined by NMR, you will
develop a mechanism for this reaction.

O
H O H
N Br
Br
OH
O CO2
H3C H H 3C H
O Et3N, DCM O

Mechanisms for alkene formation. The Z isomer of β-bromostyrene has been

synthesized according to the concerted reaction below. Sodium azide acts as a base,
removing the acidic proton to promote loss of CO2 (decarboxylation) in an E2-like
elimination that requires 8 hours at room temperature. The dibromide starting material is
obtained by anti addition of Br2 to trans-cinnamic acid.

O
Br
H C O H H
Ph H Ph
NaN3
CO2
H COOH DMF
H Ph Br
Br Br
Br
 Lab Documentation—Instructions Students—2

The Z-isomer also forms when the dibromide reacts with K2CO3 in acetone but
with K2CO3 in water a mixture of the E- and Z-isomers is obtained. An E1-like
elimination has been proposed to explain this result. The E isomer forms from the more
stable conformer of carbocation (II). The Z isomer can form either by the concerted
mechanism or from the less stable carbocation conformer (I). Carbocation formation is
promoted in water, a polar protic solvent compared to the polar aprotic solvents acetone
or DMF.
Br
Ph H K2CO3
E and Z-PhCH CHBr CO2
H COOH H2O
Br

O O

C O C O
H Ph
Ph H
H H
I Br
II
Br

H H Ph H

Ph Br H Br
Z E

The reaction with NBS. Depending upon the reaction conditions, NBS can react by
either an ionic or free radical mechanism. For example, a bromohydrin forms in an ionic
reaction of NBS with an alkene in DMSO/H2O. NBS reactions that lead to bromine
substitution at allylic or benzylic positions, as in the benzylic substitution below, proceed
by a free radical chain reaction. NBS is a source of electrophilic Br+ in the reaction you
will perform.

H3C H Br H
Ph
NBS

H2O, DMSO
H 3C
H Ph H OH
 Lab Documentation—Instructions Students—3

O O

NBS
O O
CCl4, h!, "

Br

A procedure is given below for the synthesis of β-bromo-4-methoxystyrene from

trans-4-methoxycinnamic acid. The progress of the reaction and the purity of your
product can be analyzed by TLC. Dry column vacuum chromatography (DCVC) will be
used to isolate the product. The E and Z isomers of β-bromo-4-methoxystyrene can be
distinguished by NMR, since Jtrans > Jcis for vinyl protons. GC and GC/MSD also can be
used. Your instructor will indicate which analytical methods will be applied.

Experimental procedure

COOH
NBS
FW = 178.0
Br
Me H Et3N, CH2Cl2 Me
CO2
O O
FW = 178.2 FW = 213.0

Precautions: Gloves should be worn throughout this experiment. Dichloromethane may

be harmful if absorbed through the skin, inhaled or ingested. Minimize contact with the
liquid and do not breathe its vapors. Prolonged exposure to vapors may cause cancer or
exacerbate cardiac disease. NBS is moisture sensitive and corrosive. Inhalation of TLC
grade silica gel must be avoided. Columns of TLC grade silica gel must be prepared in a
hood. The initial elution with hexane, and preferably the entire chromatographic
separation, should be performed in a hood. Hands should be washed after handling
silica gel. Dispose of the silica gel according to your instructor’s instructions.

The reaction. To a 5 mL conical reaction vial containing 3 mL of dichloromethane add

178 mg (1.00 mmol) of trans-4-methoxycinnamic acid and 214 mg (1.20 mmol) of NBS
followed by 10 µL of triethylamine (7 mol%). Add a magnetic stir bar or spin vane and
initiate stirring. As the reaction proceeds bubbles of CO2 may be observed and the
suspended solids will dissolve. A clear solution should be obtained after about ten
minutes, indicating the reaction is essentially complete. Sometimes succinimide
precipitates from the reaction mixture. Continue stirring the reaction mixture while
 Lab Documentation—Instructions Students—4

analyzing an aliquot of the reaction mixture using TLC. Use dichloromethane as the
eluting solvent (β-bromo-4-methoxystyrene Rf = 0.7 (DCM)).

Separation. In a hood fit a 15 mL medium porosity fritted glass funnel to a filter flask.
Fill the filter with TLC grade silica gel. Use the aspirator vacuum to compact the silica
gel, pressing on the silica gel surface with a cork to be sure that packing is uniform and
the top is horizontal. With the aspirator on, pre-elute the column with 15 mL of hexane.
The silica gel surface should remain covered with solvent until the solvent front has
reached the bottom of the filter. If a horizontal solvent front is not observed during this
step, re-compact the silica gel and repeat the pre-elution step. Allow the silica gel to be
sucked "dry” before turning off the aspirator. It is preferable that the remainder of the
chromatography be done in the hood. If it must be done outside the hood, minimize your
exposure to dichloromethane vapors.

Transfer the reaction mixture to the column with the aspirator off. Turn on the
aspirator to draw down the solution. Add additional dichloromethane as the last of the
reaction mixture is drawn onto the column, eventually adding a total of at least 15 mL of
dichloromethane (eluting solvent) to elute the β-bromo-4-methoxysytrene. Draw off all
of the dichloromethane so the column is “dry” before turning off the aspirator. Transfer
the dichloromethane solution collected from the column to an Erlenmeyer flask
containing anhydrous sodium sulfate. Volatile solvents evaporate at aspirator pressures,
cooling the filter flask and potentially condensing water vapor in the filter flask. While
the solution is drying, TLC analysis can be conducted to confirm satisfactory separation.

Decant the dry dichloromethane solution into a clean, dry test tube. Set aside a
small portion of the dry dichloromethane solution for GC and/or GC/MSD analysis as
required. Place the rest of the dichloromethane solution under a stream of air or nitrogen
to remove the solvent. The crude crystals of β-bromo-4-methoxystyrene obtained are
sufficiently pure for analysis.

Purification. If the product is a solid it can be recrystallized from 95% ethanol. For the E-
isomer, the melting point = 58-59°C; the Z-isomer is a liquid at room temperature, boiling point
54-56°C (1.5 mm). The crude product is sufficiently pure to determine its stereochemistry by
NMR.

Analysis. Obtain an NMR spectrum of your product dissolved in CDCl3. Identify the aryl and
vinyl hydrogens and the coupling constants of the vinyl hydrogens. The reported chemical shifts
and coupling constants for the aryl and vinyl hydrogens in E- and Z-isomers of β-bromo-4-
methoxystyrene are listed below. Based on your NMR analysis characterize the product as E, Z,
or a mixture of E, Z isomers.
 Lab Documentation—Instructions Students—5

Ha H! Ha H!

Hb Br H"
Hb

Me H" Me Br
O Ha' O Ha'

Hb' Hb'

E-"-bromo-4-methoxystyrene Z-"-bromo-4-methoxystyrene

# 6.61 (H!, d, J = 13.9 Hz), # 6.85 (Hb, Hb') # 6.31 (H!, d, J = 8.1 Hz), # 6.91 (Hb, Hb')
# 7.04 (H", d, J = 13.9 Hz), # 7.23 (Ha, Ha') # 7.00 (H", d, J = 8.1 Hz), # 7.68 (Ha, Ha')

Use a portion of the dry dichloromethane solution of your chromatographed product for
GC and/or GC/MSD analysis. Record the chromatography conditions and the retention times of
major peaks and their relative proportions as %. Identifying the major fragments in the mass
spectra is made easier by comparing your results with the fragmentation patterns of β-
bromostyrene and anisole, which can be found in mass spectral databases (NIST Chemistry
WebBook, SDBS).

Report. Your instructor will determine the exact nature of your report. It should include a
proposed mechanism that accounts for the stereochemistry you observe. Your mechanism will
be helpful in answering some of the questions below.

Questions.

1. The β-bromostyrene product is much more soluble in dichloromethane than the trans-
cinnamic acid from which it was formed. Why? How is this behavior related to the TLC results
you observed?

2. Carbocation conformers I and II may form in your reaction. Which is more stable? Is this
important in the formation of your product?

O O

C O C O
H Ph

Ph H
H II H
I Br Br
 Lab Documentation—Instructions Students—6

3. Variously substituted trans-cinnamic acids can be reacted with NBS. Predict the relative
rates of reaction for the three compounds shown below.

O O O

OH O OH OH

O 2N H3C N H
H

4. Use your mechanism to account for the following results for related reactions as reported in
the literature.

COOH Br
NBS
CO2
Et3N

H H
Ph
COOH
NBS
CH3CN/H2O, RT O O
H Br
H

5. The two-step synthesis represented below, in which the second step is microwave-
assisted, has been reported to produce Z-β-bromostyrenes. Propose a mechanism for
each step.

Br
H COOH Br2 H COOH
Ph H CHCl3
Ph H
Br

COOH
H Ph Et3N, DMF H H
mw, 1 min Ph Br
H Br
Br CO2