Low hazard small-scale synthesis and chemical analysis of high purity nitroglycerine (NG)

Article abstract of DOI:10.1039/c5ra17951c

A previously reported two-phase (99.5% fuming nitric acid/dichloromethane) batch method to prepare high purity 1,2,3-propanetriyl trinitrate (nitroglycerine, NG) was evaluated, simplified and adapted specifically for low hazard small-scale synthesis. The purity of the product, as determined by NMR spectroscopy, HPLC and IR spectroscopic analysis was found to be greater than 99%. The quick synthetic method is highly recommended when small amounts of highly pure NG are required for analytical and related purposes in the absence of a microreactor.

Full text of DOI:10.1039/c5ra17951c

View Article Online
View Journal
RSC Advances
This article can be cited before page numbers have been issued, to do this please use: A. E. Contini, N.
Flood, D. McAteer, N. Mai and J. Akhavan, RSC Adv., 2015, DOI: 10.1039/C5RA17951C.
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
Accepted Manuscripts are published online shortly after
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. This Accepted Manuscript will be replaced by the edited,
formatted and paginated article as soon as this is available.
You can find more information about Accepted Manuscripts in the
Information for Authors.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the Ethical guidelines still
apply. In no event shall the Royal Society of Chemistry be held
responsible for any errors or omissions in this Accepted Manuscript
or any consequences arising from the use of any information it
contains.
www.rsc.org/advances

Please do not adjust margins
RSC Advances
Page 1 of 6
View Article Online
DOI: 10.1039/C5RA17951C
RSC Advances
ARTICLE
Low Hazard Small-Scale Synthesis and Chemical Analysis of High
Purity Nitroglycerine (NG)
Received 00th January 20xx,
Accepted 00th January 20xx
a
a†
a
a
a
Alessandro E. Contini , Nathan Flood , Daniel McAteer , Nathalie Mai , Jacqueline Akhavan
DOI: 10.1039/x0xx00000x
1
A previously reported two-phase (99.5% fuming nitric acid/dichloromethane) batch method to prepare high purity 1,2,3-
propanetriyl trinitrate (nitroglycerine, NG) was evaluated, simplified and adapted specifically for low hazard small-scale
synthesis. The purity of the product, as determined by NMR spectroscopy, HPLC and IR spectroscopic analysis was found to
be greater than 99%. The quick synthetic method is highly recommended when small amounts of highly pure NG are
required for analytical and related purposes in the absence of a microreactor.
www.rsc.org/
the synthesis, storage, handling and processing of NG which
1
4
Introduction
have caused numerous injuries and fatalities . More recently
reported explosive incidents have occurred during the
As a key component of double base propellants and a potent
2
1
5, 16
-5
processing of NG
. The large-scale manufacture of NG is
vasodilator
nitroglycerine (1,2,3-propanetriyl trinitrate or
highly specialised and heavily regulated due to safety and
NG) is a compound of common interest to both energetic
materials and pharmaceutical scientists. Due to its
effectiveness as an energetic additive and as a medicine, it has
1
7
security concerns . Currently in the UK there is only one large-
§
scale manufacturer of NG . This creates a problem for chemists
6
-
in acquiring NG of high purity for research and development.
In recent literature the characterisation and material
properties of NG have not been thoroughly researched due to
the issues previously stated relating to purchasing and small-
scale production. The majority of the research into
been produced on the industrial scale for well over a century
8
.
Despite this, the technical literature is still scant of simple
-11
9
synthetic batch methods to prepare NG on very small-scales
less than 1 g) as may be required from time to time for
(
analytical purposes by energetic materials and pharmaceutical
research laboratories, which have no access to microreactor
technology. On such small scales, traditional mixed-acid
nitration of neat liquid glycerol can still be hazardous because
of the sharp exotherm generated by the addition of the polyol
to the chilled mixed acids. In the case of NG, the reaction
temperature and the addition rate of glycerol to the nitration
medium must be carefully controlled in order to avoid fume-
1
8, 19
characterising NG is related to propellant research
, which
mainly focuses on the properties of this nitrate ester as an
2
0, 21
energetic plasticiser
. Some published infrared spectra exist
but most of these are historic and lack the sensitivity of
1
3, 22, 23
modern instrumentation
. Historically many analytical
2
4
methods, both quantitative and qualitative have been used ,
but the most common technique for quantitative analysis is
2
5, 26
1
2
HPLC
. There are, in fact, multiple HPLC methods and
2
off and/or potential explosion due to hydrolytic processes .
Using mixed acid nitration also limits the purity and published
7,
procedures that have been developed by the pharmaceutical
2
8
29, 30
1
3
and forensic fields
however commercial NG is expensive
work does not report the potentially achievable purity . Due
to these drawbacks, synthetic chemists working in licensed
laboratories may be discouraged or even forbidden from
attempting to synthesise even minute quantities of neat NG
without prior training in nitration theory and practice. This
need not be the case if a proven and suitable small-scale
synthetic protocol is followed.
and is only available in small quantities (typically tens of
milligrams). If a safer method for small-scale synthesis (~1 g)
was developed, it would reduce the time and costs of routine
analysis.
This paper presents a new method for the synthesis of NG for
small-scale batch processes, which has a purity of 99% and is
less hazardous to prepare than the previously reported
Historically there have been many reported accidents during
9
-11
synthetic routes
.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
Please do not adjust margins

Please do not adjust margins
RSC Advances
Page 2 of 6
View Article Online
DOI: 10.1039/C5RA17951C
ARTICLE
Journal Name
1
3
14
Warning: As with other low molecular weight nitrate esters, proton); C: 71 ppm (C1 and C3) and 78 ppm (C2); N: 290 ppm (C2
dry, pure NG is extremely sensitive to impact and friction.
Despite the relatively low hazard of the suggested synthetic
procedure, both synthesis and isolation methods described
herein should only be attempted by competent chemists
working in a licenced explosives laboratory. During isolation of
the neat liquid product, Kevlar gloves and a face shield must
be worn. Scaling up the isolation of neat NG above 40 mg by
rotary evaporation behind a blast screen, could be dangerous
due to potential initiation of the liquid NG by entrained gas
bubbles, due to the formation of hot spots through adiabatic
2 2
ONO ) and 292 ppm (C1 and C3 ONO ).
Disposal
Small surplus quantities of neat NG may be safely destroyed by
re-dissolving the neat liquid in acetone, or other low toxicity
flammable solvent, for controlled burning in a ventilated fume
cupboard. Ensure that the NG is under no confinement if
burning, as a detonation would be expected even with minimal
sample.
3
1
collapse of the gas bubbles .
NMR spectroscopy
Experimental
All NMR spectra were recorded at 300 K on a Bruker Avance III
‘
NanoBay’ 400 MHz spectrometer fitted with a broadband
Synthetic procedure
BBFO probe. The chemical shifts are quoted in parts per
1
million (ppm) with reference tetramethylsilane (TMS) for H
9
9.5% fuming nitric acid (1.1 ml, 26.3 mmol), was added via a 5
ml pressure-equalising funnel to magnetically stirred 98+%
sulphuric acid (1.1 ml) in a 10 ml round bottomed flask
immersed in an ice-bath, thus ensuring that the temperature
13
6
and C spectra recorded in acetone-d .
ATR-FT-IR spectroscopy
o
of the mixture did not rise above 10 C. Dichloromethane
IR spectra were recorded on a Bruker ALPHA using Opus 7.2
(DCM) (8 ml) was then added in a single portion to the mixed
-1
o
software. The resolution was 1 cm at 128 scans. A few small
drops of the mother liquor were deposited on a glass slide, the
DCM was allowed to evaporate off, and the slide was then
Placed on a diamond attenuated total reflection (ATR)
accessary and analysed.
acid and the mixture was left stirring and cooled below 5 C.
Glycerol (500 mg, 5.4 mmol) was manually added drop-wise,
with the aid of a wide-nozzle Pasteur pipette, to the rapidly-
stirred acid /DCM mixture at such a rate as to maintain the
o
temperature below 15 C. As glycerol is not soluble in DCM, the
drops initially swirled in the rapidly stirred mixture and
gradually decreased in size as the glycerol reacted. A
concomitant increase in temperature was observed. After
about 10 min the addition was complete, the mixture was
stirred for a further 50 min, after which time the mixture lost
its opalescent appearance and became clear. It was then
transferred to a 20 ml separating funnel and the mixed acid
lower layer was run off and discarded. The organic layer was
then washed as follows: water (1 x 3 ml), 10% aqueous sodium
HPLC
Reverse phase HPLC analyses were performed using a Waters
Alliance 2695 HPLC and a Waters 996 PDA detector. The
column was a 100 x 4.6 mm Kinetex 2.6 µm C18 100 Å, sourced
o
from Phenonemex UK, and was set to 30 C. The mobile phase
2
was 50% acetonitrile (ACN) / H O at a flow rate of 1.5 ml/min.
The injection volume was 10 µl. ISO 17025 certified NG
standards were purchased from AccuStandard Laboratory
(
New Haven, USA). HPLC grade ACN was obtained from Fisher
carbonate (Na
water (3 x 2ml) and finally brine (1 x 2 ml). The washed organic
phase was dried over magnesium sulphate (MgSO ) and
2 3
CO ) (3 x 2 ml), 10% aqueous urea (1 x 3 ml),
Scientific (Loughborough, Leicestershire, UK). High purity
water was prepared by using Millipore Milli Q plus purification
system. Four calibration standards prepared in ACN ranging
from 20 to 50 ppm were injected in duplicate. The DCM
solution (0.5 ml) of the synthetic NG sample was evaporated
and 10 ml of ACN was added to the sample to prepare the
stock solution. The solution was diluted by 100 in ACN and
analysed in duplicate by HPLC. The equation of the resulting
calibration curve was used to calculate the actual amount of
NG contained in the volumetric aliquot.
4
filtered to yield a solution of 1,2,3-propanetriyl trinitrate (NG)
in DCM.
The solvent from the DCM solution (6.9wt% NG) was removed
from a 0.5 ml volumetric aliquot. This was carried out with a
standard rotary evaporator located behind a blast screen
situated in a ventilated fume cupboard. A Teflon sleeve was
placed between the male and female ground glass joints of the
pre-tared recovery flask and the rotary evaporator stem.
Working with Kevlar gloves behind the blast screen, the flask
containing small droplets of neat NG (~35 mg, as a clear,
colourless mobile oil) was weighed and immediately re-
Results and discussion
dissolved in a deuterated solvent for NMR analysis. The In our search for a relatively low-hazard batch method to
weighed mass of the droplet was used to calculate the yield of synthesise small quantities of dry, analytically pure NG, we
1
reaction and also to work out the exact concentration of the have evaluated and optimized an existing literature method
DCM solution.
with a view to synthesise milligram to gram quantities of pure
NG. Whilst the original procedure was developed to prepare
batch quantities up to 450 g of various nitrate esters free of
less stable nitrite (ester) impurities, and which relied on a
1
6
Yield:1.05 g (85%). NMR (400 MHz, acetone-d ) H: 4.95-5.00 ppm
(dd, 2.02H, C1 H
a
and C3 Ha, see Figure 1), 5.14-5.18 ppm (dd,
2
.04H, C1 H
b
and C3 H ) and 5.90-5.94 ppm (m, 1.00H, C2 methine
b
2
| J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 3 of 6
PleaseRd So Cn oA t da vd aj un s ct ems argins
View Article Online
DOI: 10.1039/C5RA17951C
Journal Name
ARTICLE
Redox potentiometric probe to regulate the glycerol addition
rate, we have adapted the method to prepare much smaller
amounts of product down to 250 mg, without using
microreactors and without potentiometric control.
Analytical
Method
NG mass contained in
0.5ml volumetric aliquot
of stock DCM solution
35.0mg
Yield Concentration/Purity
Theoretical
Gravimetric
HPLC
-
35.0mg
Our method relies on two-phase (mixed acid and DCM)
nitration of glycerol, whereby an inert and dense chlorinated
solvent acts as a temperature-moderating heat sink during the
reaction, removing the nitrate ester as it forms from the
34.4mg
99%+
-
-
34.5mg
-
34.5mg
-
NMR
99%+
nitration medium, maximising the reaction yield by minimizing Table 1 - Results of NG analysis
oxidative side reactions, and most importantly, de-sensitising
1
The 400 MHz H NMR spectrum of our product indicates purity
the nitrate ester for safer handling. This is in contrast to
traditional methods of NG synthesis where the product is
stored as an aqueous emulsion which poses an explosive
1
3
greater than 99% (only C satellites are visible when the
intensity of the spectrum is increased). The unsymmetrical
signal shown in Figure 1 can be assigned when considering the
symmetrical nature of the NG molecule. Pro-chirality at C2
renders the protons of both methylene groups non-equivalent
and this results in a more complex spectrum than would be
6
hazard upon separation . The product is typically obtained as a
solution in dichloromethane, which is neutralised with
aqueous bicarbonate and then repeatedly washed with water
to remove less nitrated and/or oxidative side products. The
final dry solution is non-flammable, and may be safely stored
in a dark cupboard at room temperature for several months
without any explosive risk.
1
3
expected from a simple AB spin system. The C spectrum
Figure 2) displays only two product signals indicative of the C2
and the isosynchronous C1 and C3. The analysis of the product
(
1
4
by N NMR spectroscopy (Figure 3) (previously unreported)
shows C1 and C3 nitrate esters as a broad peak at 292ppm,
which is approximately double the intensity of a very close
peak resonating at 290 ppm, which was attributed to the
nitrate ester at C2.
From a licensing, storage and transport point of view this
method also has the advantage that the NG is immediately
dissolved in DCM. According to the United Nations Economic
Commission for Europe’s (UNECE) European Agreement
concerning the International Carriage of Dangerous Goods by
3
2
Road (ADR 2015) the desensitised non-flammable NG
solution can be given a UN no. 3357 and is class 3D based on
3
the ADR 2015 .
2
During preparation of the mixed acid on scales up to 1.0 g, we
found that drop-wise addition of 99.5% nitric acid to chilled
(0°C) 98% sulphuric acid is more practical than adding
sulphuric acid to chilled nitric acid, as a consequence of the
viscosity of the former which prevents it from dripping freely
through the narrow channel of a small dropping funnel.
Although the reverse addition order is not recommended on
larger scales, the acid dilution exotherm was negligible when a
simple ice-water bath was used to chill the magnetically stirred
sulphuric acid.
1 and 3
2
§§
1
13 14
Gravimetric , HPLC and H/ C/ N NMR spectroscopic
analyses of the product (Figures 1-5) confirmed that this
method gives NG of very high purity (>99%) and in excellent
yield. The analysis did not reveal the presence of unreacted
1
glycerol, less nitrated by-products (1,2- and/or 1,3- Figure 1 - H NMR spectrum (in acetone-d
dinitroglycerine) or nitrite esters, confirming that
6
) of NG
potentiometric control during glycerol addition is not required
to obtain analytical purity on very small-scales (Table 1).
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
Please do not adjust margins

Please do not adjust margins
RSC Advances
Page 4 of 6
View Article Online
DOI: 10.1039/C5RA17951C
ARTICLE
Journal Name
1
and 3
2
1
3
Figure 2 - C NMR spectrum (in acetone-d
6
) of NG
3500
3000
2500
2000
1500
1000
500
Wavenumber cm-1
Figure 5 - Infrared spectrum of NG
1
and 3
-
1
Observed peaks (cm )
Functional Group
C-H Stretch
3
2
2
1
1
1
1
1
1
1
1
1
024
966
916
631
457
428
376
293
264
087
052
007
2
C-H Stretch
C-H Stretch
-NO
-NO
2
2
Asymmetric Stretch
Asymmetric Stretch
C-H Bend/Rock
C-H Bend/Rock
-NO
-NO
2
Symmetric Stretch
Symmetric Stretch
C-O Stretch
2
14
6
Figure 3 - N NMR spectrum (in acetone-d ) of NG
C-O Stretch
Figure 4 depicts the HPLC chromatogram of the NG sample,
showing the absence of impurities. This is further supported by
Figure 5, which displays the ATR-FT-IR spectrum of the NG
sample. Some key absorption frequencies observed in the NG
IR spectrum are presented in Table 2.
N-O Linkage π Bond Stretching
C-H Bend
8
99
20
49
00
68
91
8
2
-NO Wag
7
7
6
5
C-H Bend
C-H Bend
C-H Bend
C-H Bend
0.010
0.005
0.000
Table 2 - Infrared spectrum main peak assignments of NG
0.50
1.00
1.50
Minutes
2.00
2.50
Figure 4 - HPLC chromatogram of synthetic NG extracted at 254nm
4
| J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 5 of 6
PleaseRd So Cn oA t da vd aj un s ct ems argins
View Article Online
DOI: 10.1039/C5RA17951C
Journal Name
ARTICLE
Figure 6 shows NMR spectroscopic analysis of a two-year-old
solution containing approx. 20wt% of our synthesised NG. The
NG did not reveal any degradation of the product after this
time; this was also confirmed by HPLC (Figure 7) and ATR-FTIR-
§
§§
IR .
1
Figure 6 - H NMR spectrum (in acetone-d
6
) of NG showing no degradation over
two years (red – date of synthesis and blue – aged two years)
Figure 8 - NG detonating under a hammer blow
Conclusion
0.04
A previously published two-phase nitration method was
successfully simplified and adapted to the small-scale (up to
0
.02
0.00
1.0 g) synthesis of NG for analytical purposes. The product was
0.20
0.40
0.60
0.80
1.00
1.20
1.40
1.60
1.80
2.00
2.20
2.40
2.60
2.80
3.00
Minutes
obtained in excellent yield and high purity, as determined by
gravimetric analysis, HPLC, ATR-FT-IR and NMR spectroscopy.
dF ieg gu r rae d 7a t –i o Hn Pa Lf Ct e cr h2 r oy me a ar ts ogram of synthetic NG extracted at 254 nm showing no Given the simplicity, relatively low hazard and cost involved,
this synthetic method is highly recommended, whenever small
quantities of highly pure NG (and possibly other nitrate esters)
If required, small quantities of up to 50 mg of neat product
are required for analytical and related purposes in the absence
may be isolated as a colourless mobile oil by rotary
of a microreactor.
evaporation of small volumetric aliquots of the
dichloromethane mother liquor. Because of the very high
purity and the total absence of water, the neat liquid NG
obtained by this method has extremely high sensitiveness,
particularly to impact. A small droplet deposited on a metal
anvil can be readily initiated by application of a gentle hammer
blow (Figure 8), confirming the absence of less nitrated
products and water that would greatly de-sensitise NG
towards impact.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
Please do not adjust margins

Please do not adjust margins
RSC Advances
Page 6 of 6
View Article Online
DOI: 10.1039/C5RA17951C
ARTICLE
Journal Name
Acknowledgements
Thanks to the British Broadcasting Corporation (BBC) for
21. D. A. Winkler, Propellants, Explosives, Pyrotechnics, 1985, 10, 43-
46.
assisting in photographing the ignition by impact of NG (Image 22. F. Pristera, Analytical Chemistry, 1953, 25, 844-856.
hosted at BBC Motion Gallery).
23. F. Pristera, M. Halik, A. Castelli and W. Fredericks, Analytical
Chemistry, 1960, 32, 495-508.
Thanks to Gavin Dunhill (Cranfield University) for his advice on
hazard classifications.
24. V. Y. Grigor’eva, O. A. Efremenko and Y. Y. Kharitonov,
Pharmaceutical Chemistry Journal, 2004, 38, 562-568.
25. R. Martel, A. Bellavance-Godin, R. Lévesque and S. Côté,
Chromatographia, 2010, 71, 285-289.
Notes and references
§
Roxel (UK Rocket Motors) Ltd
§§ Gravimetric analysis is the physical weighing of the NG residue after evaporating 26. X. Xu, M. Koeberg, C. Kuijpers and E. Kok, Science & Justice
,
the DCM solvent from a 0.5ml aliquot of stock solution
2014, 3-21.
27. L. Gelber, Journal of Pharmaceutical Sciences, 1980, 69, 1084-1086.
§
§§ Results not shown, as there was no change from the spectra shown in Figure 5
2
8. A. Halasz, S. Thiboutot, G. Ampleman and J. Hawari, Chemosphere,
1
2
3
4
.
.
.
.
C. Marken, C. Kristofferson, M. Roland, A. Manzara and M. Barnes,
Synthesis, 1977, 484-485.
2010, 79, 228-232.
29. J. B. F. Lloyd, Journal of the Forensic Science Society, 1986, 26,
341-348.
M. Pröbster and R. H. Schmucker, Acta Astronautica, 1986, 13, 599-
6
05.
L. Ignarro, Proceedings of the National Academy of Sciences, 2002,
9, 7816-7817.
J. R. Parratt, Journal of Pharmacy and Pharmacology, 1979, 31, 801-
09.
30. F. M. Green, T. L. Salter, P. Stokes, I. S. Gilmore and G. O'Connor,
Surface and Interface Analysis, 2010, 42, 347-357.
9
31. F.P. Bowden and A.D. Yoffe, Initiation and Growth of Explosion in
Liquids and Solids, Cambridge-Hitachi, 1985.
8
32. United Nations Economic Commission for Europe, European
Agreement concerning the International Carriage of Dangerous
Goods by Road (ADR 2015) 2015, 141.
5
6
.
.
G. Thatcher, Chemical Society Reviews, 1998, 27, 331-337.
A.S Gordon and P.C.W Art, Manufacture of explosives, US Pat.,
US2140897 A, 1938.
7
.
F. Nathan, J. Thomson and W. Rintoul, Apparatus for the
manufacture of nitroglycerin, Report US702325 A, Google Patents,
US, 1902.
8
9
.
.
C. A. Woodbury and W. C. Holmes, Industrial & Engineering
Chemistry, 1935, 27, 632-637.
S. Braune, S. Steinhofer, P. Poechlauer, R.W.E.G. Reintjens, N.T.W.
Linssen and M. Thathagar, Formation of nitrate esters in
microreactors and millireactors using
a continuous product
extraction in a turbulent flow regime, US Pat., US 12/808,829, 2011.
1
1
1
0. J. Hogan, Nature, 2006, 442, 352.
1. A. Turley, Chemistry World, RSC, Cambridge, 2012.
2. E. Camera, G. Modena and B. Zotti, Propellants, Explosives,
Pyrotechnics, 1982, 7, 66-69.
1
1
3. R. Schneider and M. Hanson, An Infrared Spectroscopic Study Of
The Vapor Adsorption Of Nitroglycerin (NG) On Chrysotile
Asbestos, Colorado, 2000.
4. UK Health and Safety Executive, Explosives Incidents Database
Advisory Service,
http://webcommunities.hse.gov.uk/connect.ti/explosives/groupHome,
Accessed 7/1/2015.
1
1
1
5. Munitions Safety Information Analysis Center, Lettre du MSIAC
NATO, 2nd Quarter 2011.
,
6. Munitions Safety Information Analysis Center, Lettre du MSIAC
NATO, 4th Quarter 2008.
,
7. UK Health and Safety Executive, Explosives Regulations 2014,
http://www.hse.gov.uk/explosives/new-regulations.htm, Accessed
/8/2015.
3
1
1
2
8. S. Heng, T. Pan, Y. Kong and Z. Liu, Propellants, Explosives,
Pyrotechnics, 1991, 16, 31-35.
9. F. Volk, G. Wunsch and D. Müller, Propellants, Explosives,
Pyrotechnics, 1982, 7, 53-57.
0. Yu M. Lotmentsev and D. V. Pleshakov, Propellants, Explosives,
Pyrotechnics, 1997, 22, 203-206.
6
| J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins