Josh Stolz, Chem 213
Synthetic #2 FFR
Benzodiazepine Synthesis
Introduction
Benzodiazepines are organic molecules that are used to treat a variety of physical and
psychological disorders. Benzodiazepines work within the central nervous system to increase
the presence of the neurotransmitter GABA. 1 GABA is an inhibitory neurotransmitter that
decreases the activity of affected neurons, which results in muscle relaxation, reduced anxiety,
and sleepiness. Benzodiazepines have been used as antidepressants, sedatives, anti-anxiety
medications, and sleeping aids. 2 They have also been widely used within military hospitals to
temporarily treat PTSD. 3 In addition, new research shows that benzodiazepines might be useful
in fighting viral infections and aiding cancer and cardiovascular research. 2
Benzodiazepines consists of two rings; a benzene ring attached to a seven-atom ring in
which two of the seven atoms are nitrogen.2 These molecules are therefore considered
heterocycles. 4 The Structure of a benzodiazepine (specifically 2,3-dihydro-2,2,4-trimethyl-1H1,5-benzodiazepine) can be seen in Figure 1.
Figure 1. 2,3-dihydro-2,2,4-trimethyl-1H-1,5-benzodiazepine
In the current experiment 2,3-dihydro-2,2,4-trimethyl-1H-1,5-benzodiazepine was
synthesized from o-phenylenediamine and two equivalents of acetone. This was accomplished
through a condensation reaction. The condensation reactions are of great importance in organic
chemistry since it is one of the few ways to create a carbon-to-carbon bond. 5 One example is
the aldol condensation reaction in which two carbonyl compounds (aldehydes or ketones) react
with an acid or base to create one larger organic molecule. 5 Condensation reactions are also
seen in biological pathways such as in carbohydrate metabolism. 5 The mechanism for this
specific condensation reaction can be seen in figure 2.
Figure 2 Mechanism
In this mechanism sulfamic acid acts as a catalyst, allowing an amino group from ophenylenediamine to attack the carbonyl carbon of acetone. This creates a negative charge on
the oxygen in acetone, which then deprotonates the attacking amino group. The oxygen atom of
sulfamic acid then pushes its electrons onto the amino group, which uses this lone pair of
electrons to from a double bond with the carbonyl carbon from acetone. The oxygen atom from
acetone is kicked out in this step as a water molecule is formed. This sequence happens a second
time in which the second amino group of o-phenylenediamine acts as the attacking nucleophile
and likewise becomes an imine. After this second reaction with acetone, a tautomerization of
one imine group occurs. Next, the electrons of the tautomerized nitrogen atom push to form a
double bond with the adjacent carbon. This causes the existing double bond of the alpha carbon
to attack the carbon of the adjacent imine. This forms a ring. The attacked nitrogen atom now
has a free lone pair of electrons. These electrons deprotonate the other nitrogen group of the
benzodiazepine to create 2,3-dihydro-2,2,4-trimethyl-1H-1,5-benzodiazepine.
The purpose of this lab was to synthesize 2,3-dihydro-2,2,4-trimethyl-1H-1,5benzodiazepine from o-phenylenediamine and two equivalents of acetone in the presence of
sulfamic acid. The crude product from this reaction was then purified by re-crystallization. By
carrying out this reaction it was possible to learn how general condensation reactions are
performed and to gain a higher level of mastery of re-crystallization as a purifying technique.
The final product was analyzed by melting point, infrared spectroscopy (IR), and nuclear
magnetic resonance spectroscopy (NMR).
Experimental
2,3-dihydro-2,2,4-trimethyl-1H-1,5-benzodiazepine. O-phenylenediamine (0.527 g, 4.87
mmol), sulfamic acid (0.057 g, 6.3 mmol), and acetone (0.81 mL, 11 mmols) were placed in a 20
mL screw cap vial and stirred until a yellow homogenous mixture was formed (2 hours). The
reactant mixture was added to a solution of ethyl acetate (10 mL) and distilled water (30 mL) in a
separator funnel. The aqueous layer of the mixture was extracted with ethyl acetate (2 x 20 mL).
The resulting orange organic phases were combined in a 100 mL beaker along with sodium
sulfate (20 min). The solution was decanted into a 50 mL beaker and dried with a stream of
nitrogen. The fluffy brown mixture was recrystalized in a 1:1 ethyl acetate/ hexanes solution.
The remaining yellow, brown crystals were isolated through vacuum filtration (0.282 g, 30.8%
yield); mp 125-128 ˚C; 1H NMR (60 MHz, CDCl3) δ (ppm) 7.27-6.72 (m, 4H), 3.28 (s, 1H), δ
2.36 (s, 3H), 2.22 (s, 2H), 1.33 (s, 6H); 1H NMR (400 MHz, CDCl3) δ (ppm) 7.3 (s, 1H), 7.2 (m,
1H), 7.0 (m, 1H), 6.7 (m, 1H), 3.0 (s, 1H), 2.4 (s, 3H), 2.2 (s, 2H), 1.4 (s, 6H); 13C NMR (400
MHz, CDCl3) δ (ppm) 172.46, 140.71, 137.83, 126.72, 125.44, 122.05, 121.70, 77.30, 68.41,
44.99, 30.41, 29.79; IR (ATR) max (cm-1) 3290.64, 3017.94, 2958.70, 1471.61-1429.41,
1373.77, 1314.90.
Results and Discussion
2,3-dihydro-2,2,4-trimethyl-1H-1,5-benzodiazepine was synthesized from ophenylenediamine and two equivalents of acetone in the presence of sulfamic acid. This
synthesis was accomplished from two condensation reactions and a ring closure. The crude
product was then recrystallized and isolated by vacuum filtration; 0.282 g of final product was
obtained for a 30.8% yield. Through the observed integration values and chemical shift of the
NMR spectroscopy and the observed peaks of the IR spectroscopy, it is suggested that 2,3dihydro-2,2,4-trimethyl-1H-1,5-benzodiazepine was synthesized with a decent level of purity.
The benzodiazepine product was analyzed by both 60MHz and 400 MHz 1H NMR
spectroscopys. Only the 400 MHz NMR will be discussed since these spectroscopys correspond
with each other. There are multiplets at δ (ppm) 7.3, 7.2, 7.0, and 6.5; each peak contains an
integration value of 1. These peaks are most likely from aromatic hydrogen. The exact splitting
of each of these hydrogen atoms is unclear, however it does seem to be a doublet or triplet. This
splitting seems to matches the expected NMR of the benzodiazepine product. The hydrogen
bonded to the carbon in a conjugated system with the imine is most likely at δ 7.3 (HA figure 4),
while the hydrogen of the aromatic carbon closest to the secondary amine is likely located at δ
7.2 (HD figure 4). The other two aromatic hydrogen atoms (HC, HB figure 4) are at δ 7.0 and δ
6.5. While this observed NMR does fit with the expected NMR of the benzodiazepine product,
the staring material also has four aromatic hydrogen atoms that would closely resemble this
NMR. There is a singlet present at δ (ppm) 3.0 that has an integration value of 1. This is most
likely the hydrogen of a secondary amine. A secondary amine is found in the product 2,3dihydro-2,2,4-trimethyl-1H-1,5-benzodiazepine (HE figure 4). While the starting product ophenylenediamine does have an amino group that might have a similar chemical shift, this group
would have an integration value of 6 and not the observed value of 1. Another singlet is found at
δ (ppm) 2.36 with an integration value of 3.0. This might be a methyl group that is shifted
downfield. This matches the NMR of the expected product that contains a methyl group that is
part of an imine (HI, figure 4). A singlet with an integration value of 2 is found at δ (ppm) 2.2.
This may be the peak from a secondary carbon. This peak is also congruent with the expected
NMR of the product. There is a final peak at δ (ppm) 1.4 that contains an integration value of 6.
This peak may be from two equivalent methyl groups such as the ones found in the expected
NMR of the benzodiazepine product. This observed NMR matches the predicted NMR of the
starting material only at peaks δ (ppm) 7.3, 7.2, 7.0, and 6.5. However, this observed NMR
exactly matches the predicted NMR of the benzodiazepine product. In addition, the total
integration value of 16 hydrogen atoms present match the number of hydrogen atoms present in
the benzodiazepine product. It can be concluded with some certainty that the starting material is
not present and it is highly likely that 2,3-dihydro-2,2,4-trimethyl-1H-1,5-benzodiazepine was
synthesized.
The benzodiazepine was also analyzed by 13C NMR spectroscopy. There is a peak at δ
(ppm) 172.46. This peak corresponds to the carbon that is apart of the azomethine present in the
benzodiazepine product (CA, figure 5). Due to the far downfield shift of this peak it is unlikely
that it could be caused from the staring material o-phenylenediamine. There are peaks present at
δ (ppm) 140.70, 137.83, 126.72, 125.44, 122.05, and 121.70 (C:B,G,F,C,D,E, figure 5). It is
likely that these peaks are from carbon atoms of a benzene ring. It is possible that the peak at δ
140.70 is caused from the aromatic carbon adjacent to an imine of the benzodiazepine product
(CB) and the peak at δ 137.83 (CG) is caused from an aromatic carbon adjacent to a secondary
amine found in the benzodiazepine product. While the starting material may have a similar
expected NMR, it is not able to account for the two downfield aromatic carbons. However, this
observed NMR does match the expected NMR of the benzodiazepine product. There are also
peaks at δ (ppm) 77.30, 76.99, 76.67. CDCl3 may be the cause of these peaks. There is a peak
present at δ (ppm) 68.41. This peak closely matches the saturated carbon of the benzene product
(CI). Another peak is found at δ (ppm) 44.99. This peak might be caused from the vinylic
methyl group found in the product (CL). Finally two peaks are present at δ (ppm) 30.41 and
29.79 (CK, CL respectively). These peaks correspond with the secondary carbon atom and two
methyl groups found in the product. Like the 400 MHz NMR, the starting product only matches
this NMR in the first few peaks, while the expected NMR of the product closely matches this
observed NMR. From this analysis it can be concluded that there is little or no starting material
present and that it is very possible that the observed product is 2,3-dihydro-2,2,4-trimethyl-1H1,5-benzodiazepine.
In addition to NMR spectroscopy, IR spectroscopy was also used to analyze the
Benzodiazepine product. These results can be seen in figure 6. There is a sharp peak at 3209.64
(cm-1). This peaks indicates the presences of a secondary amine group. Short multiple peaks are
found around 3017.94 (cm-1), which seem to indicate aromatic hydrogen. A sharp long peak is
found at 2958.70 (cm-1), which is most likely the carbon, carbon, hydrogen stretch found in all
IR. Of these peaks it is clear that an aromatic and that a secondary amine group are present, both
of these are found in the benzodiazepine product. Only the aromatic hydrogen is present in the
starting material. There is a bend found between 1471.61-1429.41 (cm-1). This seems to be the
stretch of a secondary carbon to two hydrogen atoms. There are also peaks found at 1373.77 and
1314.90 (cm-1). These peaks may indicate the presence of methyl groups. In the benzodiazepine
product a secondary carbon and methyl groups are present; these groups are absent in the starting
material. From the observed IR it is clear that an aromatic, secondary amine, secondary carbon,
and methyl groups are present in the final product. This IR matches the expected IR of the
benzodiazepine product, and suggests that 2,3-dihydro-2,2,4-trimethyl-1H-1,5-benzodiazepine
may have been successfully synthesized.
While the spectroscopy was used to identify what final product was present, melting
point was used to identify the purity of this product. The observed mp was 125-128˚C, while the
literature value of the benzodiazepine product is 137-139 ˚C. 6 The literature value of ophenylenediamine is 98-102 ˚C. 7 From the observed melting points, it is likely that there is little
or no starting material in the final product. However, this 9˚C difference in melting points does
suggest a level of impurities. It is possible that some ethyl acetate is still present in final product.
In the future, less solution could be used during recrystallization in order to get a more pure final
product. It is worth noting however, that when this experiment was run in other laboratories
under similar conditions, a melting point of only 120-122 ˚C was observed. 8 It can be concluded
that the final product was found to have a higher level of purity when compared to the results of
other laboratories, but still has impurities as seen by a 9 ˚C difference between observed and
literature value melting points. The mass of the benzodiazepine product was also measured.
Of the theoretical 0.971 g of benzodiazepine product possible, only 0.282 g of the
benzodiazepine was produced for a 30.8% yield. The % yield may be low for the fact that the
reaction did not go to completion. If there was a way to remove the product and shift the
equilibrium toward the products then there could have been a higher % yield. However,
removing product in this particular lab while the reaction continues to run might be impossible.
Furthermore, % yield is expected to be low in this experiment for the fact that recrystallization
was used to purify the crude product. Recrystallization is a technique that increases purity while
sacrificing amount of product produced. In this experiment, it is common for the % yield to be
between 5 and 55 %. 4 If the benzodiazepine was purified by column chromatography then there
could have been a higher yield. In the future, column chromatography could be used to increase
the yield.
Conclusion
2,3-dihydro-2,2,4-trimethyl-1H-1,5-benzodiazepine was successfully synthesized from ophenylenediamine and two equivalents of acetone in the presence of sulfamic acid. This was
achieved through two condensation reactions, one of the few ways in organic chemistry to create
a carbon-to-carbon bond. While there may seem to be a low % yield (0.282 g, 30.8%) this is
within the expected range for this experiment. 4 Both the observed 1H NMR and the observed 13C
NMR match the expected results for the benzodiazepine product. The observed IR indicate the
presence of a secondary amine, an aromatic, a secondary carbon, and methyl groups, all of which
are present in the benzodiazepine product. While the melting point may seem low compared to
the literature value (9 ˚C difference), it is higher than what has been reported in other labs. 8 This
synthesis was successful in producing 2,3-dihydro-2,2,4-trimethyl-1H-1,5-benzodiazepine and
teaching the importance of condensation reactions.
References
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Haefley, W.; Journal of Nature. 1981, 290, 514-516
(2) Singh, J.; Dhakarey, R. K. S.; Singh, S. V.; Saxena, J. K.; Dwivedi, A. K.; Chemistry and
Biology Interface. 2012, 2, 5, 339-346
(3) Capehart, B. P.; J. Clin. Psychiatry. 2012, 73(3), 307-309
(4) Fletcher, J. T.; Boriraj.; Journal of Chemical Education. 2010, 87, 631-633
(5) Mcmurry, J. Organic Chemistry, 8th ed; Belmont: California; pp 904-906, 928-930
(6); 2,3-dihydro-2,2,4-trimethyl-1H-1,5-benzodiazepine MSDS. Sigma Aldrich [Online]
http://www.sigmaaldrich.com/catalog/product/aldrich/s411337?lang=en&region=US
(accessed 4/10/13)
(7) o-phenylenediamine; MSDS. Sigma Aldrich [Online] http://www.sigmaaldrich.
com/catalog/product/sigma/p9029?lang=en&region=US (accessed 4/10/13)
(8) Sharma, S.; Prasad, D. N.; Singh, R. K.; J. Chem. Pharm. Res. 2011, 3(5), 382-389