Diazo-Transfer Reagent 2-Azido-4,6-dimethoxy-1,3,5-triazine Displays Highly Exothermic Decomposition Comparable to Tosyl Azide

Article abstract of DOI:10.1021/acs.joc.9b00269

2-Azido-4,6-dimethoxy-1,3,5-triazine (ADT) was reported recently as a new "intrinsically safe" diazo-transfer reagent. This assessment was based on differential scanning calorimetry data indicating that ADT exhibits endothermic decomposition. We present DSC data on ADT that show exothermic decomposition with an initiation temperature (T_init) of 159 °C and an enthalpy of decomposition (?H_D) of ?1135 J g^-1 (?207 kJ mol^-1). We conclude that ADT is potentially explosive and must be treated with caution, being of comparable exothermic magnitude to tosyl azide (TsN₃). A maximum recommended process temperature for ADT is 55 °C.

Full text of DOI:10.1021/acs.joc.9b00269

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Note
Diazo Transfer Reagent 2-Azido-4,6-Dimethoxy-1,3,5-Triazine (ADT)
Displays Highly Exothermic Decomposition Comparable to Tosyl Azide
Sebastian P. Green, Andrew D. Payne, Katherine M.
Wheelhouse, Jason P. Hallett, Philip W. Miller, and James A. Bull
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00269 • Publication Date (Web): 05 Apr 2019
Downloaded from http://pubs.acs.org on April 6, 2019
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The Journal of Organic Chemistry
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Diazo Transfer Reagent 2-Azido-4,6-Dimethoxy-1,3,5-Triazine
(ADT) Displays Highly Exothermic Decomposition Comparable to
Tosyl Azide
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Sebastian P. Green,†,‡ Andrew D. Payne,§ Katherine M. Wheelhouse,║ Jason P. Hallett,*,‡ Philip W.
Miller,*,† James A. Bull*,†
† Department of Chemistry, Imperial College London, Molecular Sciences Research Hub, White City Campus, 80 Wood
Lane, London, W12 0BZ, UK
‡ Department of Chemical Engineering, Imperial College London, South Kensington Campus, Exhibition Road, London,
SW7 2AZ, UK
§ Process Safety, Pilot Plant Operations, GlaxoSmithKline, GSK Medicines Research Centre, Gunnels Wood Road, Steven-
age, Hertfordshire, SG1 2NY, UK
║ API Chemistry, Product Development & Supply, GlaxoSmithKline, GSK Medicines Research Centre, Gunnels Wood
Road, Stevenage, Hertfordshire, SG1 2NY, UK
Supporting Information Placeholder
p-Dodecylbenzenesulfonyl azide (p-DBSA) was introduced as
a safer alternative to TsN3 owing to its lower enthalpy of decom-
position (ΔHD), reduced impact sensitivity and higher thermal
stability.2 More recently, p-acetamidobenzenesulfonyl azide (p-
ABSA) has found extensive use as a diazo transfer reagent. p-
ABSA has a similar safety profile to p-DBSA, however the great-
er polarity differences between p-ASBA and typical activated
methylene substrates facilitate product separation.5 A polystyrene-
supported benzenesulfonyl azide (PSS-BSA) has also been pro-
posed as a safer reagent but suffers from high cost and poor atom
economy.6
ABSTRACT: 2-Azido-4,6-dimethoxy-1,3,5-triazine (ADT) was
reported recently as a new ‘intrinsically safe’ diazo transfer rea-
gent. This assessment was based on Differential Scanning Calo-
rimetry (DSC) data indicating that ADT exhibits endothermic
decomposition. We present DSC data on ADT that show exo-
thermic decomposition with an initiation temperature (Tinit) of
159 °C and an enthalpy of decomposition (ΔHD) of –1135 J g–1 (–
207 kJ mol–1). We conclude that ADT is potentially explosive and
must be treated with caution, being of comparable exothermic
magnitude to tosyl azide (TsN3). A maximum recommended pro-
cess temperature for ADT is 55 °C.
As a replacement for the more reactive but sensitive and explo-
sive triflyl azide (TfN3), nonafluorobutanesulfonyl azide (NfN3)
has been demonstrated to be insensitive, less exothermic and can
be isolated and stored while still maintaining the high reactivity.7
Imidazole-1-sulfonyl azide 1 HCl salts were proposed to be safe
until samples spontaneously exploded,8 highlighting the need for
rigorous safety investigations for novel azide reagents. Later in-
vestigations discovered that the H2SO4 salt was insensitive and
safer to handle, however its preparation still required isolation of
the highly impact sensitive imidazole-1-sulfonyl azide.9 Recently,
an improved route to 1·H2SO4 that circumvents the isolation of
imidazole-1-sulfonyl azide has been reported.10 Thermal analysis
data for these selected diazo transfer reagents is given in Table
1.11 Less hazardous reagents would be highly attractive for all
applications as substitution is an effective chemical hazard control
measure.12
Diazo transfer reagents effect the transfer of N2 to activated
methylene substrates and amines to generate diazo and azide
compounds respectively. Although a range of organoazide diazo
transfer reagents exist (Figure 1), sulfonyl azides are the most
widely used.1 Sulfonyl azides are, however, highly energetic due
to the thermodynamically favourable formation of gaseous de-
composition products, and some are reported to be impact sensi-
tive and potentially explosive.2,3 Improving the safety profile of
diazo transfer reagents has been a key driver in this field since the
initial use of tosyl azide (TsN3) over 50 years ago.4
O
S
O
O
S
O
O
S
O
O O
O
N3
N3
N3
S
F3C
N3
N
11
H
TsN3
TfN3
-DBSA
-ABSA
p
p
N3
F
F O O
O
X
HN
O
F3C
S
N
N
N
S
N3
N3
F
F F F
MeO
N
OMe
1
NfN3
ADT
Imidazole-1-sulfonyl azide
Figure 1. Selected Diazo Transfer Reagents
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to exhibit explosive propagation. We also present a rationale for
the differing conclusions drawn by Ma from their data.
Table 1. Diazo Transfer Reagents with Improved Safety
Profile11
1
2
3
4
5
6
7
8
9
ADT was prepared in one step from 2-chloro-4,6-dimethoxy-
1,3,5-triazine (CDMT) or in two steps from 2,4,6-trichloro-1,3,5-
triazine (TCT) as reported by Ma (Scheme 2).16 Both the interme-
diate CDMT and precursor TCT are commercially available pep-
tide coupling reagents. DSC analysis on TCT and CDMT was
recently reported by Pfizer and neither was considered to be po-
tentially impact sensitive or explosive (For TCT: Tinit = 360 °C,
ΔHD = –36 J g–1; For CDMT: Tinit = 161 °C and ΔHD = –513 J g–
1).18
en-
try
diazo
transfer
reagent
Tinit
Tonset
(°C)
ΔHD
ΔHD
ref
(°C)
(J g–1) (kJ mol–1)
1
2
3
4
5
TsN3
120
151
120
156 a
–1696 –334
2
p-DBSA
p-ABSA
–703
–720
–275
–419
–247
–173
–183
–136
2
155 b
166
5
PSS-BSA 130
NfN3
120 c
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Scheme 2. Synthesis of ADT
141
7c
a from reference 13. b from reference 14. c from reference 15.
Ma recently reported the novel azido triazine diazo transfer re-
agent, 2-azido-4,6-dimethoxy-1,3,5-triazine (ADT). This was
shown to be effective in the transfer of N2 to a variety of activated
methylene positions (Figure 1 and Scheme 1).16 The reaction was
reported to proceed rapidly in DMSO using various bases, and
achieved excellent yields of diazo compounds with a variety of
substrates. We observed similarly successful results with this
reagent.
Ma reported thermal analysis of ADT by Thermogravimetric
Analysis (TGA) and DSC (Figure 2; Table 2 entry 1).16,19 For
both techniques a 2.5 mg sample was heated at 5 °C min–1 but
further details of the procedure were not provided.
In our study, ADT was analysed by DSC using 5 mg of sample,
weighed into a stainless steel high-pressure crucible, sealed, and
analysed with a temperature ramp of 5 °C min–1 (for more detail,
see Experimental Section). The results for initiation temperature
(Tinit), extrapolated onset temperature (Tonset) and enthalpy of
decomposition (ΔHD) were measured for two samples and aver-
aged. This analysis was repeated on a different machine at Glax-
oSmithKline (GSK) using a slightly different method involving
gold-plated high-pressure crucibles and a 2 °C min–1 temperature
ramp. Table 2 gives the raw and averaged data from both sets of
experiments compared to those obtained by Ma.
Scheme 1. Diazo Transfer Reaction with ADT
ADT (1.1 equiv)
N2
base (40 mol%)
R
R'
R
R'
DMSO
25 °C, 2-6 min
77-98%
Selected examples:
N2
N2
N2
N2
R = COCH3
COPh
R = OtBu
CH3
OEt
O
O
R
R
COOEt
Ph
P(O)(OEt)2
Ph
O
O
O
The report was particularly notable since the diazo transfer rea-
gent, ADT, was described as being intrinsically safe: insensitive
to impact and exhibiting an endothermic decomposition (ΔHD
A representative DSC plot for ADT is given in Figure 3 for
comparison with the originally reported plot in Figure 2. The
melting point occurs at a similar temperature and then a signifi-
cant exotherm of –1135 J g–1 is observed. This is in clear contrast
with the results from Ma.
=
+30 kJ mol–1, see Figure 2). Such properties avoid the risk of a
thermal runaway. The endothermic decomposition was deter-
mined by Differential Scanning Calorimetry (DSC), which
measures the energy difference between a sample crucible and an
inert reference. DSC is a valuable screening tool in process safety
to investigate thermal hazards. The original work also demon-
strated ADT to be insensitive to impact and friction using stand-
ard tests described by the UN Recommendations on the Transport
of Dangerous Goods.17
Figure 2. Reported DSC and TGA plots for ADT from Ma.
Reproduced from Xie, S.; Yan, Z.; Li, Y.; Song, Q.; Ma, M. J.
Org. Chem. 2018, 83, 10916–10921. Copyright 2019 American
Chemical Society.
Figure 3. DSC Plot of ADT (Table 2, Entry 3)
As part of a broader study on energetic diazo transfer reagents
and diazo compounds, and given the interest to the academic and
industrial communities of a reagent considered safe, we examined
ADT. Here we report our findings from DSC and TGA-MS exper-
iments and conclude, contrary to Ma’s report, that ADT exhibits
exothermic decomposition of a magnitude that may be predicted
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Table 2. DSC data of ADT and Other Diazo Transfer Reagents11
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entry
DSC Result
melting point Tinit
Tonset
(°C)
Tpeak
(°C)
ΔHD
ΔHD
(°C)
(J g–1)
(kJ mol–1)
(Tpeak, °C)
1
Ma et al
84.73
87.84
87. 68
87.76
approx 130 a
approx. 150 a
174
218
216
217
206
205
206
178
186
186
186
+166 b
–1103
–1161
–1135
–1248
–1231
–1240
+213
+30.3
–201
–211
–207
–227
–224
–226
+39
2
ADT result 1 c
ADT result 2 c
ADT avg
GSK ADT result 1 d 87.5
GSK ADT result 2 d 86.5
158
159
159
142
144
143
110
131
125
128
187
187
187
178
178
178
135
158
158
158
c
3
4
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GSK ADT avg
87.0
8
ADT open crucible e 85.5
tosyl azide result 1 c
tosyl azide result 2 c
tosyl azide avg
9
–1088
–1025
–1057
–215
–202
–209
10
11
a
Estimated from DSC plot. Calculated from reported ΔHD kJ mol–1 value. Using DSC method A (see experimental). d Using DSC
b
e
method B (lower measured temperatures are due to a slower scan rate). Using DSC method C with unsealed crucible. See Figure 4 for
plot.
The most likely reason for the endothermic transition observed
in the previous report is gas loss from the sample, occurring dur-
ing decomposition.20 As gaseous products from decomposition
escape the sample crucible they remove heat from the system,
resulting in detection of an endotherm. This hypothesis was tested
by performing DSC analysis on a sample of ADT in an open cru-
cible. The resulting plot was found to closely match the DSC plot
reported by Ma (Figure 4 and Table 2, Entry 5). Here the endo-
thermic gas loss completely obscured the exothermic decomposi-
tion (1135 J g–1). Indeed, the magnitude of exotherm upon de-
composition is similar to that observed for tosyl azide using the
same DSC method (Table 2 Entries 9-11).2 Since tosyl azide is
known to be explosive,2,21 ADT therefore could also present a
potential explosion hazard.
magnitude to fully obscure the significant exotherm. From the
EGMS trace, the following mass ions were detected above base-
line levels, in abundance order with assignments: 28 (N2, normal-
ised to 100% intensity), 14 (N, 7.7%), 40 (NCN, 2.2%), 29
(15N≡N, 0.76%), and trace mass ions (<0.1% relative intensity) 27
(HCN), 20, 15 (15N or CH3), 18 (H2O), 12 (C), 30 (NO), 36, 44
(CO2), 54, 70. A previously reported analysis of the pyrolysis
products of 2,4,6-triazido-1,3,5-triazine found only N2 gas and
polymeric C3N5.2 residue.22
Figure 5. TGA plot of ADT.
Application of the Yoshida correlation23 allows the prediction
of explosive propagation in material (eq 1). From this equation,
which correlates the Tonset and Q (the energy released upon de-
composition, in cal g–1) with results from known explosive, bor-
derline explosive and non-explosive materials. An output with a
positive value predicts the material can detonate (propagating an
explosive shockwave). A negative value would predict the materi-
al, though exothermic, is not capable of explosive decomposition.
Figure 4. DSC Plot of ADT with unsealed crucible
EP = log10 (Q) – 0.38[log10(Tonset – 25)] – 1.67 (1)
TGA coupled to Evolved Gas Mass Spectrometry (EGMS) was
used to investigate the decomposition products. Using a 5 °C min–
heating rate, the TGA plot in Figure 5 shows mass loss com-
mencing as early as 85 °C, significant mass loss occurring from
150-200 °C (Tonset 158.8 °C, the inflection point analogous to Tpeak
at 182.7 °C and ending at 200.1 °C) and leaving a residue of
3.23% of the original mass at 300 °C. Approx 90% of the mass of
ADT is converted to gas by 205 °C; it is this particularly high
proportion of gas loss that gives rise to an endotherm of sufficient
(where Q is the energy released upon decomposition in cal g–1)
1
There is also a modified form used by Pfizer which is more
conservative, reducing the Q term by 25% and using Tinit (eq 2).18
EP = log10 (Q) – 0.285[log10(Tinit – 25)] – 1.67 (2)
Applying the average values obtained from the DSC of ADT
gave the outputs given in Table 3. The Yoshida correlation is
close to the prediction threshold and the more conservative Pfizer-
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modified correlation predicts explosive propagation. It is therefore
ommended, for example by using an adiabatic technique such as
Accelerating Rate Calorimetry.
1
2
3
4
5
6
7
8
highly recommended that further explosivity screening with either
a specially modified Accelerating Rate Calorimeter (ARC)24 or
definitive UN Class 1 testing17 is conducted before using ADT in
a large scale process. Note that even if a material cannot propa-
gate explosive detonation, it may still cause explosive rupture of a
vessel upon decomposition due to rapid gas evolution.
EXPERIMENTAL SECTION
DSC Experimental Terminology: Tinit is defined by the tem-
perature at which the heat flow is measured to be > 0.01 W g–1
from the baseline. Tonset is defined by the intersection of the ex-
trapolated maximum peak slope and the baseline. ΔHD is obtained
by integration of the peak. Averaged DSC results reported where
individual results have <1% difference from the average for Tinit
and Tonset and <5% difference from the average for ΔHD.
Table 3. Application of Yoshida EP Correlation to DSC
results
9
en-
try
DSC result
Yoshida EP Pfizer-modified
EP
10
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1
2
3
ADT avg a
GSK ADT avg b
tosyl azide avg a
-0.08
-0.03
-0.07
0.13
0.18
0.13
DSC Method A: DSC analysis was performed using a TA In-
struments Q2000 DSC with LNCS. Approx 5 mg was weighed
into a reusable PerkinElmer B0182901 stainless steel high-
pressure crucible with disposable gold-plated copper seal rated to
150 bar and sealed under air with the appropriate B0182864 seal-
ing tool. After equilibrating at 25 °C, samples were heated at 5
°C min–1. Data analysis was conducted using TA Instruments
Universal Analysis 2000 software version 4.5.0.5.
a Using DSC Method A. b Using DSC Method B.
From a process safety perspective an exotherm of this magni-
tude is cause for concern. Though the compound was demonstrat-
ed to be insensitive to impact, there is still potential for thermally-
initiated decomposition. Process Safety at GSK use a formula to
determine a maximum recommended safe process temperature,
defined by Stoessel, given in eq 3.25
DSC Method B: DSC analysis was performed using a Mettler
Toledo DSC 823e. Approx 5 mg was weighed into a Mettler To-
ledo ME-26731 gold-plated 40 µl high-pressure crucible with seal
insert and lid rated to 150 bar, and sealed under air with the ap-
propriate sealing press. After equilibrating at 25 °C, samples were
heated at 2 °C min–1. Data analysis was conducted using Mettler
Toledo STARe software version 12.00 build 5342.
TD24 = 0.7 × Tinit – 46
(3)
The recommendation is based on zero-order Arrhenius kinetics
of a runaway thermal decomposition reaction, where TD24 is the
temperature at which the Time to Maximum Rate under adiabatic
conditions (TMRad) is 24 h and there is therefore minimal risk of
triggering runaway decomposition. Tinit is used as it represents an
approx 0.01 W g–1 exothermic baseline shift as detected in the
DSC experiment.
DSC Method C (open crucible): DSC analysis was performed
using a TA Instruments Q2000 DSC with LNCS. Approx 2 mg
was weighed into TA Instruments 901683.901 Tzero aluminium
crucible and 901684.901 Tzero hermetic lid, sealed under air with
the appropriate 901600.901 Tzero sample press and 901608.904
Tzero hermetic die set and then pierced with a needle to leave two
holes of approx 1 mm diameter. After equilibrating at 25 °C,
samples were heated at 5 °C min–1. Data analysis was conducted
using TA Instruments Universal Analysis 2000 software version
4.5.0.5.
Using the lowest averaged Tinit obtained for ADT (measured
with the 2 °C min–1 temperature ramp), the maximum recom-
mended safe process temperature is 55 °C, rounded to the nearest
5 °C. Applying the same process for tosyl azide gives a maximum
recommended safe process temperature of 45 °C.26 Additionally,
adequate thermal control must be in place to prevent overheating
and consideration must also be given to evolved gas in a potential
thermal runaway scenario. In any case, it is advisable to minimise
the risk profile of a process firstly by selection of a less hazardous
reagent if available.
TGA-MS Experimental Method: TGA-MS was performed on
a Netzsch TG209 F1 Libra TGA and Netzsch QMS 403 D Aëolos
(cross beam EI) EGMS. Approx 20 mg was weighed into an open
Al2O3 crucible. A temperature ramp of 5 °C min–1 and purge gas
flow of 40 ml min–1 N2 was used. For the EGMS, a Fast SCB scan
of mass range 10-70 was used. A plot of all mass ions was ob-
tained and filtered to display those that showed a significant in-
crease upon decomposition of ADT, determined by the TGA. The
baseline was determined by the average of mass ion intensity
from 10 EGMS cycles from 8.32 min (67 °C) to 10.45 min (77
°C) and the decomposition gases determined by subtraction of the
baseline for each mass ion from the average of 3 EGMS cycles
from 32.88 min (189 °C) to 33.30 min (192 °C) for that mass ion.
EGMS traces and full data can be found in the SI.
In summary, ADT was recently developed as an effective diazo
transfer reagent to form diazo compounds with activated methyl-
enes using an inorganic base in DMSO. However, it was also
reported as being ‘intrinsically safe’ due to an endothermic de-
composition. We have demonstrated that the DSC result previous-
ly presented does not accurately represent the exothermic decom-
position of ADT. Analysis of the decomposition of compounds
where gas evolution may occur should be performed in sealed
crucibles capable of containing the pressure generated to mini-
mise the possibility of misleading results. Our data shows ADT
has a highly exothermic decomposition where Tinit is 159 °C,
Tonset is 187 °C and ΔHD is –1135 J g–1 (–207 kJ mol–1). Although
ADT has a higher initiation and onset temperature than tosyl azide
and has been demonstrated by Ma to be insensitive to impact and
friction, care must be taken to avoid decomposition of ADT dur-
ing a reaction or other processing of this compound (e.g. drying,
recrystallizing), as the large exotherm and evolved gas present a
similar explosion hazard. A maximum process temperature of 55
°C is therefore recommended based upon DSC data alone. How-
ever, it should be recognised that for materials that exhibit such a
hazardous decomposition profile, further study is strongly rec-
General Experimental Methods. All non-aqueous reactions
were run under an inert atmosphere (nitrogen) with flame-dried
glassware using standard techniques. Anhydrous solvents were
obtained by filtration through drying columns (MeCN) or used as
supplied (MeOH, DMSO). Commercial reagents were used as
supplied. Flash column chromatography was performed using
230-400 mesh silica with the indicated solvent system. Analytical
thin-layer chromatography was performed on precoated, glass-
backed silica gel plates. Visualization of the developed chromato-
gram was performed by UV absorbance (254 nm), or aq potassi-
um permanganate stain. Infrared spectra (FTIR) were recorded in
reciprocal centimeters (cm–1) using a FTIR ATR spectrometer.
Nuclear magnetic resonance spectra were recorded on a 400 MHz
spectrometer. Chemical shifts for 1H NMR spectra are recorded in
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The Journal of Organic Chemistry
(10) Potter, G. T.; Jayson, G. C.; Miller, G. J.; Gardiner, J. M. An Up-
parts per million with the residual protic solvent resonance as the
internal standard (chloroform: 7.27 ppm). Data were reported as
follows: chemical shift (multiplicity, integration). 13C NMR spec-
tra were recorded with complete proton decoupling. Chemical
shifts are reported in parts per million with the solvent resonance
as the internal standard (13CDCl3: 77.0 ppm).
dated Synthesis of the Diazo-Transfer Reagent Imidazole-1-Sulfonyl
Azide Hydrogen Sulfate. J. Org. Chem. 2016, 81, 3443–3446.
(11) For definitions of Tintit and Tonset and how they are obtained from
the DSC data, see Experimental Section: DSC Experimental Terminology.
(12) An alternative approach to improve safety regimes is to generate
and react diazo transfer reagents in continuous flow. Such processes avoid
the isolation and handling of hazardous reagents and significantly reduce
total reactor volumes. For selected examples of the use of diazo transfer
reagents in flow, see: a) Gérardy, R.; Winter, M.; Vizza, A.; Monbaliu, J.-
C. M. Assessing Inter- and Intramolecular Continuous-Flow Strategies
towards Methylphenidate (Ritalin) Hydrochloride. React. Chem. Eng.
2017, 2, 149–158. b) Deadman, B. J.; O’Mahony, R. M.; Lynch, D.;
Crowley, D. C.; Collins, S. G.; Maguire, A. R. Taming Tosyl Azide: The
Development of a Scalable Continuous Diazo Transfer Process. Org.
Biomol. Chem. 2016, 14, 3423–3431. c) O’Mahony, R. M.; Lynch, D.;
Hayes, H. L. D. D.; Ní Thuama, E.; Donnellan, P.; Jones, R. C.; Glennon,
B.; Collins, S. G.; Maguire, A. R. Exploiting the Continuous in Situ Gen-
eration of Mesyl Azide for Use in a Telescoped Process. Eur. J. Org.
Chem. 2017, 6533–6539.
(13) Cardillo, P.; Gigante, L.; Lunghi, A.; Fraleoni-Morgera, A.; Zani-
rato, P. Hazardous N-Containing System: Thermochemical and Computa-
tional Evaluation of the Intrinsic Molecular Reactivity of Some Aryl Az-
ides and Diazides. New J. Chem. 2008, 32, 47–53.
(14) Müller, S. T. R.; Murat, A.; Maillos, D.; Lesimple, P.; Hellier, P.;
Wirth, T. Rapid Generation and Safe Use of Carbenes Enabled by a Novel
Flow Protocol with In-Line IR Spectroscopy. Chem. Eur. J. 2015, 21,
7016–7020.
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Synthetic Procedures:
ADT was prepared according to the report from Ma et al.16
CDMT is commercially available.
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ASSOCIATED CONTENT
Supporting Information
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The Supporting Information is available free of charge on the
ACS Publications website.
DSC plots of ADT, TGA plot of ADT, EGMS traces, synthetic
details and 1H and 13C NMR spectra for ADT. (PDF)
All characterization data for synthesized compounds, raw DSC
and TGA-EGMS data for ADT can be found at
https://doi.org/10.14469/hpc/4946.
AUTHOR INFORMATION
Corresponding Authors
(15) Zhu, S.-Z. Synthesis and Reactions of Fluoroalkanesulfonyl Az-
ides and N,N-Dichlorofluoroalkanesulfonamides. J. Chem. Soc. Perkin
Trans. 1 1994, 113, 2077–2081.
(16) Xie, S.; Yan, Z.; Li, Y.; Song, Q.; Ma, M. Intrinsically Safe and
Shelf-Stable Diazo-Transfer Reagent for Fast Synthesis of Diazo Com-
pounds. J. Org. Chem. 2018, 83, 10916–10921.
(17) An excellent description of these tests written for chemists can be
found in Section 1.4 of the following book: Banert, K.; Brase, S. Organic
Azides: Syntheses and Applications, 1st ed.; John Wiley & Sons, Ltd:
Chichester, UK, 2010. Normally the purview of energetic materials scien-
tists, see UN Recommendations on the Transport of Dangerous Goods:
Manual of Tests and Criteria (ST/SG/AC.10/11.Rev.6, ISBN 978-92-1-
139155-8, link: http://www.unece.org/trans/areas-of-work/dangerous-
goods/legal-instruments-and-recommendations/un-manual-of-tests-and-
criteria/rev6-files.html); 2015.
(18) Sperry, J. B.; Minteer, C. J.; Tao, J.; Johnson, R.; Duzguner, R.;
Hawksworth, M.; Oke, S.; Richardson, P. F.; Barnhart, R. W.; Bill, D. R.;
Giusto, R. A.; Weaver, J. D. Thermal Stability Assessment of Peptide
Coupling Reagents Commonly Used In Pharmaceutical Manufacturing.
Org. Process Res. Dev. 2018, 22, 1262–1275.
(19) In a previous report without experimental details, the decomposi-
tion of ADT was found to occur at 195 °C. Kayama, R.; Hasunuma, S;
Sekiguchi, S.; Matsui, K. The Thermal Reactions of Azido-1,3,5-triazines.
Bull. Chem. Soc. Jpn. 1974, 47, 2825-2829.
(20) An alternative explanation could be that ADT evaporates from the
open crucible before decomposition. However, due to the high melting
point and reported TGA of the decomposition of similar compound 2,4,6-
triazido-1,3,5-triazine, this seems less likely (See reference 22).
(21) a) Hazen, G. G.; Bollinger, F. W.; Roberts, F. E.; Russ, W. K.;
Seman, J. J.; Staskiewicz, S. 4-Dodecylbenzenesulfonyl Azides. Org.
Synth. 1996, 73, 144. b) Rewicki, D.; Tuchscherer, C. 1-Diazoindene and
Spiro[Indene-1,7’-Norcaradiene]. Angew. Chem. Int. Ed. Engl. 1972, 11,
44–45.
(22) Nedel’ko, V. V.; Korsunskii, B. L.; Larikova, T. S.; Chapyshev, S.
V.; Chukanov, N. V.; Yuantsze, S. Thermal Decomposition of 2,4,6-
Triazido-1,3,5-Triazine. Russ. J. Phys. Chem. B, 2016, 10, 570–575.
(23) Yoshida, T.; Yoshizawa, F.; Itoh, M.; Matsunaga, T.; Watanabe,
M. Prediction of Fire and Explosion Hazard for Reactive Chemicals (I):
Estimation of Explosive Properties of Self-Reactive Chemicals from SC-
DSC Data. Kogyo Kayak. 1987, 48, 311–316 (British library translation
available). A salient application of Yoshida’s correlations can be found in
the Pfizer peptide coupling work (See reference 18).
*E-mail: j.hallett@imperial.ac.uk.
*E-mail: philip.miller@imperial.ac.uk.
*E-mail: j.bull@imperial.ac.uk.
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENTS
For financial support, we gratefully acknowledge GSK, the Phar-
macat Consortium and EPSRC for iCASE studentship funding,
and The Royal Society [University Research Fellowship,
UF140161 (to JAB) and Research Grants (RG150444 and
RGF\EA\180031)].
REFERENCES
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(2) Hazen, G. G.; Weinstock, L. M.; Connell, R.; Bollinger, F. W. A
Safer Diazotransfer Reagent. Synth. Commun. 1981, 11, 947–956.
(3) a) Tuma, L. D. Identification of a Safe Diazotransfer Reagent.
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Diazotransfer Reagents. Synlett 1996, 5, 407–413.
(4) Regitz, M. New Methods of Preparative Organic Chemistry. Trans-
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(5) Baum, J. S.; Shook, D. A.; Davies, H. M. L.; Smith, H. D. Diazo-
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Synth. Commun. 1987, 17, 1709–1716.
(6) Green, G. M.; Peet, N. P.; Metz, W. A. Polystyrene-Supported Ben-
zenesulfonyl Azide: A Diazo Transfer Reagent That Is Both Efficient and
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(7) a) Zhu, S.-Z. Synthesis and Reactions of Fluoroalkanesulfonyl Az-
ides and N,N-Dichlorofluoroalkanesulfonamides. J. Chem. Soc. Perkin
Trans. 1 1994, 113, 2077–2081. b) Chiara, J. L.; Suárez, J. R. Synthesis of
α-Diazo Carbonyl Compounds with the Shelf-Stable Diazo Transfer Rea-
gent Nonafluorobutanesulfonyl Azide. Adv. Synth. Catal. 2011, 353, 575–
579. c) Suárez, J. R.; Collado-Sanz, D.; Cárdenas, D. J.; Chiara, J. L.
Nonafluorobutanesulfonyl Azide as a Shelf-Stable Highly Reactive Oxi-
dant for the Copper-Catalyzed Synthesis of 1,3-Diynes from Terminal
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(8) Goddard-Borger, E. D.; Stick, R. V. An Efficient, Inexpensive, and
Shelf-Stable Diazotransfer Reagent: Imidazole-1-Sulfonyl Azide Hydro-
chloride. Org. Lett. 2007, 9, 3797–3800. A correction was later published
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(24) Bodman, G. T.; Chervin, S. Use of ARC in Screening for Explo-
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Verlag GmbH: Weinheim, Germany, 2008, Chapter 3.
(9) Fischer, N.; Goddard-Borger, E. D.; Greiner, R.; Klapötke, T. M.;
Skelton, B. W.; Stierstorfer, J. Sensitivities of Some Imidazole-1-Sulfonyl
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(26) This maximum recommended process temperature was determined
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