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Potential Safety Hazards Associated with Using

N,N‑Dimethylformamide in Chemical Reactions
Qiang Yang,* Min Sheng, and Yongliang Huang

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ABSTRACT: N,N-Dimethylformamide (DMF) is frequently used as a solvent because of its unique physical properties that allow it
to solubilize both organic and inorganic substances. It has also found broad applications as a catalyst for a variety of chemical
transformations and as a donor for many functional groups in synthetic organic chemistry. However, DMF is incompatible with a
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wide variety of substances and has resulted in many incidents over the years. Analysis of literature information indicates that those
incompatible substances can be categorized as acids, bases, halogenated reagents, oxidants, and reductants. This comprehensive
review of the potential hazards of using DMF in chemical reactions will serve as an educational resource to promote awareness of
such safety hazards in the broader chemistry community and encourage scientists to develop appropriate control strategies to
mitigate the potential safety risks associated with the use of DMF in chemical reactions.
KEYWORDS: N,N-dimethylformamide, DMF, explosion hazards, thermal instability, autocatalytic decomposition, thermal runaway,
exothermic decomposition

1. INTRODUCTION Scheme 1. DMF as a Multipurpose Building Block in

Synthetic Organic Chemistry
N,N-Dimethylformamide (DMF) (CAS no. 68-12-2, boiling
point 153 °C), a clear, colorless liquid with a faint amine odor,
was first synthesized by Verley in 1893 by heating a mixture of
sodium formate and dimethylammonium chloride.1 Commer-
cially, DMF is produced by reacting methanol (MeOH) and
ammonia (NH3) to give a dimethylamine (Me2NH)/
trimethylamine (Me3N) mixture after isolation and treating
the Me2NH/Me3N mixture with carbon monoxide (CO).2
The DMF market is poised to grow from $637.8 million in
2017 to $792.1 million by 2022 at a compound annual growth
rate (CAGR) of 4.43%. The growth of the DMF market is
primarily driven by increased demand from various industries
such as chemical, electronics, pharmaceutical, agrochemical,
etc.3
DMF is widely used as a polar aprotic solvent in synthetic
organic chemistry to effect a broad range of chemical reactions
because of its excellent dissolution property that allows it to
solubilize both organic and inorganic species. More impor-
tantly, over the years DMF has found broad applications in a database showed no detectable exothermic decomposition at
wide variety of chemical transformations as a catalyst4 and as a temperatures up to 400 °C when a sample of pure DMF was
multipurpose building block to deliver a variety of functional evaluated under an atmosphere of nitrogen (N2) in the
headspace (Table 1, entry 1). Similarly, accelerating rate
groups, including N,N-dimethylamido [−CON(CH3)2], N,N-
calorimetry (ARC) evaluation of 5.28 g of pure DMF using a
dimethylamino [−N(CH3)2], formate (HCO2−), formyl
Hastelloy ARC cell with a phi factor of 1.72 showed that pure
(−CHO), carbonyl (>CO), cyano (−CN), oxygen (O), and
hydrogen (H) moieties (Scheme 1).5
DMF is reported to be stable at ambient temperature. Received: July 10, 2020
However, it undergoes slow decarbonylation near its boiling Published: August 6, 2020
point of 153 °C to release Me2NH and CO, and therefore,
distillation of DMF is generally conducted under reduced
pressure at a lower temperature below its boiling point.6
differential scanning calorimetry (DSC) data found in our

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Table 1. Historical Thermal Stability Data on DMF and Its min after the addition of KOMe, and then faded away
Mixtures from Corteva’s Database gradually until complete disappearance after 10−25 min
(Scheme 2, blue). It is worth noting that the formation of a
onset energy
evaluation temp. release variety of radicals and products was also observed by Kroh and
entry sample tool conditions (°C) (J/g)a,b Burzynska when DMF was irradiated with ionizing rays
1 DMF DSC N2 none up to 400 °C (Scheme 2, purple).11 These observations provided important
2 air 170 −109 evidence to support the hypothesis that the decomposition of
3 ARC N2 none up to 350 °C DMF occurs via an autocatalytic radical mechanism under
4 50% HCl (37%) + HOM 26 °C − −151 certain conditions.
5 50% DMF DSC N2 60 −188 A variety of substances can induce the decomposition of
6 40 mg of H3PO4 + HOM 20 °C − −10 DMF because of its unique reactivity, and this has resulted in
7 35 mg of DMF 32 17 many incidents over the years, with reports dating back to as
8 DSC N2 140 50 early as the 1960s. Further analysis of these incidents indicated
9 253 > −217 that these substances can be categorized as acids, bases,
10 SO3−DMF DSC air 32 28 halogenated reagents, oxidants, and reductants. This compre-
11 complex 114 −254 hensive review of potential safety hazards associated with DMF
12 228 −646 will serve as an educational resource to promote awareness of
13 12.5 mg of LiH + DSC air 188 −632 the potential hazards associated with the use of DMF in the
325 μL of DMF broader chemistry community and to encourage researchers to
14 40% NaOt-Bu + HOM 25 °C − −45 perform safety evaluations of reactions using DMF and develop
15 60% DMF DSC N2 165 84 appropriate control strategies to mitigate such safety risks.
16 275 −159
17 50% SOCl2 + 50% HOM 25 °C − −140
DMF 2. POTENTIAL SAFETY HAZARDS WITH DMF
18 DSC N2 111 −488
19 12.6% NBS + ARC N2 61 −126 An exothermic reaction is generally maintained at the desired
87.4% DMFc process temperature (TP) with external cooling until reaction
20 11 mg of KMnO4 HOM 36 °C − −820 completion is reached. However, a higher reaction temperature
21 + 11.6 μL of DSC N2 60 −71
DMF results when the heat generation rate surpasses the heat
22 208 −193 removal rate in cases of insufficient cooling. If all of the
a
Negative values indicate exotherms, and positive values indicate reactants are accumulated and the reaction continues under
endotherms. bThe energy was normalized to the total mass of the final adiabatic conditions, the reaction temperature would reach the
mixture. cFinal pressure at 200 °C: 3.95 bar. maximum temperature of a synthesis reaction (MTSR), which
is equal to TP + ΔTad, where ΔTad is the adiabatic temperature
DMF is stable at temperatures up to 350 °C under an rise. When the MTSR exceeds the onset temperature of
atmosphere of N2 in the headspace (Table 1, entry 3). reaction mixture decomposition, a secondary reaction could be
Because of their similar physical properties, DMF has been triggered to potentially result in runaway scenarios or even
frequently used as a replacement for dimethyl sulfoxide explosions (Figure 1).12
(DMSO)7 in chemical reactions to mitigate the potential The reaction heat generation rate and the resulting ΔTad are
explosion hazards associated with the thermal decomposition generally evaluated using reaction calorimeters such as a micro
of DMSO.8 However, as a compound carrying formyl and reaction calorimeter (μRC),13 an EasyMax HF Cal heat flow
amide functional groups, DMF is prone to many decom- calorimeter,14 and/or an RC-1 reaction calorimeter.15 Potential
position pathways such as hydrolysis, oxidation, reduction, thermal decomposition reactions are characterized with
etc.9 Øpstad et al. observed the formation of DMF radicals by DSC,16 a thermal screening unit (Tsu),17 an advanced reactive
electromagnetic resonance (EMR) and NMR analyses when system screening tool (ARSST),18 rapid detection of
anhydrous DMF was treated with potassium methoxide exothermic reaction (RADEX),19 ARC,20 and/or a vent sizing
(KOMe).10 It was found that DMF radicals were formed package (VSP).18 It needs to be pointed out that, in general,
instantaneously, reached a maximum concentration within 2−4 decomposition can start at temperatures well below the

Scheme 2. Reported Radicals and Products during DMF Decomposition

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Figure 1. Potential reaction safety hazard scenarios. Reproduced from
ref 8d. Copyright 2020 American Chemical Society.
detected onset temperature because of instrument sensitivity.
It is crucial for scientists to understand the reaction calorimetry
and heat generation rate of the desired reaction as well as the
thermal instability hazards of reaction mixtures to ensure that
the reaction is performed at a safe temperature (e.g., 100 °C
below the decomposition onset temperature detected by
DSC).21
2.1. Potential Safety Hazards of DMF in the Presence
of Acids. DMF is hydrolyzed in the presence of acids to afford
Me2NH and formic acid (HCO2H), which has been employed
as an “in situ” source of Me2NH to effect a variety of chemical
transformations.22 However, the hydrolysis of DMF in the
presence of acids, especially strong acids, can be hazardous
because the hydrolysis product, HCO2H, can further
decompose to release noncondensable gases such as CO,
carbon dioxide (CO2), hydrogen (H2), etc. The decomposition
of HCO2H can be fast and violent in the presence of a wide
variety of catalysts that are frequently employed in chemical
transformations.23
DMF reacts violently with aqueous HCl when they are
mixed at ambient temperature. A heat of mixing (HOM) of
−151 J/g was observed when 1 mL of 37 wt % aqueous HCl
was mixed with 1 mL of DMF at 26 °C in a μRC (Table 1,
entry 4). Mixtures of aqueous HCl and DMF further
decompose violently when heated at slightly elevated temper-
atures. For example, DSC evaluation of a 1:1 mixture of 37 wt
% aqueous HCl and DMF showed an exothermic event
starting at 60 °C with a total energy release of −188 J/g when
performed under an atmosphere of N2 in the headspace (Table
1, entry 5).
DMF also decomposes exothermically in the presence of
phosphoric acid (H3PO4) at elevated temperatures. DSC
evaluation of a mixture of 40 mg of H3PO4 and 35 mg of DMF
revealed two endothermic events starting at 32 and 140 °C,
respectively (Table 1, entries 7 and 8), and an exothermic
event starting at 253 °C (Table 1, entry 9). The decomposition
onset temperature was significantly reduced compared with the
>400 °C onset temperature of pure DMF. The heat release for
the exothermic event was determined to be greater than −217
J/g because the experiment was terminated at 400 °C before
the exothermic event was complete.
Sulfur trioxide (SO3)−DMF complex has found wide
applications as a sulfonation reagent24 and been employed in
large scale N-sulfations.25 However, it has been reported that a
bottle of SO3−DMF complex exploded during storage.26
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Although the exact root cause was not identified, it was
suspected that SO3 reacted with moisture to form sulfuric acid
(H2SO4), which subsequently decomposed DMF to release
CO and other porducts. DSC evaluation of a sample of SO3−
DMF complex indicated two significant exothermic events
starting at 114 and 228 °C when the experiment was
conducted under an atmosphere of air in the headspace. The
energy releases for these two exothermic events were −254 and
−646 J/g, respectively (Table 1, entries 11 and 12). It is worth
noting that the potential safety hazard associated with the
thermal instability of SO3−DMF complex is underappreciated,
as indicated by the fact that this potential explosion hazard has
not yet been clearly specified in the safety data sheets (SDSs)
from major suppliers.27
The formation of noncondensable and flammable gaseous
products during the decomposition of DMF in the presence of
acids, especially strong acids, drastically increases the severity
of the hazards because of the potential for reactor over-
pressurization or even fire if the reaction system is not properly
vented and inerted. It is imperative for scientists to understand
the safety hazards associated with the decomposition of DMF
in the presence of acids and design proper control strategies to
mitigate these inherent safety risks.
2.2. Potential Safety Hazards of DMF in the Presence
of Bases. Pure DMF decomposes appreciably if it is allowed
to stand at ambient temperature for a prolonged time in the
presence of a strong base such as potassium hydroxide (KOH),
sodium hydroxide (NaOH), or calcium hydride (CaH2).28 The
decomposition of DMF in the presence of strong bases to
release Me2NH has been employed as an in situ source of
Me2NH to effect a variety of chemical transformations. For
example, Garcia et al. employed hydroxide-assisted decom-
position of DMF as an in situ source of Me2NH in the
nucleophilic aromatic substitution of aryl fluorides and
chlorides 11 with Me2NH (Scheme 3).29 Pertersen et al.
Scheme 3. Hydroxide-Assisted Decomposition of DMF as
an In Situ Source for Me2NH for Nucleophilic Aromatic
Substitution of Aryl Fluorides and Chlorides
developed a continuous flow nucleophilic aromatic substitu-
tion with Me2NH generated in situ by decomposition of DMF
with aqueous ammonia.30 Typically, a stream of a solution of
aqueous ammonia in DMF was mixed with a solution of the
aryl halide in DMF and passed through a high-temperature
(240 °C) stainless steel reactor to form the desired product 14
(Scheme 4).
Sodium hydride (NaH) has been widely used as a base to
facilitate a wide range of chemical transformations because it is
easy to handle and store and often offers predictable reactivity
and high atom efficiency.31 One of the most commonly used
solvents with NaH is DMF because of its complementary
physical properties that allow it to solubilize both organic and
inorganic compounds. Studies have shown that the role of
NaH in the chemical transformations in DMF is to act not just
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Scheme 4. Nucleophilic Aromatic Substitution with Me2NH
Generated In Situ by Decomposition of DMF with Aqueous
Ammonia
as a base but also as a source of hydride that reacts with DMF
exothermically or participates in many chemical reactions.32
The potential safety hazards associated with the thermal
instability of DMF in the presence of NaH were first reported
in the 1960s. In a communication to Tetrahedron Letters in
1965, Powers et al. reported an energetic decomposition of
DMF during NaH-mediated cleavage of the formyl group in
DMF (Scheme 5).33 Shortly after that, Brimacombe et al.
reported similar exothermic decomposition of DMF during the
alkylation of carbohydrate 16 in DMF using NaH as the base
(Scheme 6).34
Scheme 5. Cleavage of the Formyl Group of DMF by NaH
Scheme 6. Alkylation of 16 in the Presence of NaH in DMF
The hazards associated with the thermal instability of NaH/
DMF present greater risks on scale because the rate of heat
removal decreases drastically with increasing reaction volume.
In 1982, Buckley et al. at SmithKline Beckman reported an
uncontrolled self-heating in a 2500 L-scale condensation
reaction employing NaH in DMF, which triggered the reactor’s
rupture disk.35 Subsequent ARC studies by the researchers
indicated that mixtures of NaH with either DMF or N,N-
dimethylacetamide (DMAc) started to self-heat at temper-
atures as low as 26 °C, resulting in a rapid temperature
Figure 2. ARC heat rate and pressure vs temperature profiles of NaH/DMF mixtures. Reproduced from ref 37. Copyright 2019 American
Chemical Society.
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increase to 80 °C, at which point the cooling capacity of the
pilot-plant reactor was overwhelmed. The onset temperature of
decomposition was between 40 and 50 °C when a mixture of
NaH and carefully dried DMF was tested by ARC. An
analogous large-scale incident was reported by DeWall at
Burdick and Jackson Laboratories in the same year, in which
uncontrolled self-heating of a NaH/DMF reaction mixture
began at 40 °C and rapidly increased the batch temperature to
>100 °C in less than 10 min.36 The batch temperature could
not be controlled even when full cooling was applied to the
reaction vessel, resulting in evaporation of the majority of
DMF before the reaction subsided. The author noted that this
reaction had been conducted many times smoothly prior to
this incident, highlighting the unpredictable nature of this
decomposition.
In order to understand the impact of NaH on the
decomposition of DMF, Yang et al. at Corteva Agriscience
performed a detailed evaluation of the thermal decomposition
of NaH/DMF mixtures (Figure 2).37 ARC analysis of a
mixture consisting of 15.8% NaH in mineral oil (60 wt %) and
84.2% DMF revealed a significant exothermic event starting at
76.1 °C, which produced a total energy of −528.4 J/g with a
maximum self-heating rate of 7.23 °C/min. The onset
temperature of decomposition was lowered to 39.8 °C when
the mass ratio of 60 wt % NaH in mineral oil was increased to
41%, affording a peak self-heating rate of 634.7 °C/min and a
total energy release of more than −601.8 J/g.
Noncondensable gases were formed during the decom-
position of DMF in both cases, as evidenced by the presence of
substantial cool-down pressures after testing. Evolved gas
analysis (EGA) micro-GC analysis of the gaseous phase of
decomposition indicated that H2, CO, methane (CH4),
ethylene (CH2CH2) or acetylene (HCCH), and CO2
were among the gaseous products, suggesting that the
decomposition potentially proceeds via a more complicated
radical mechanism. The formation of noncondensable gaseous
products drastically increases the severity of the hazards
because of the potential for reactor overpressurization and
flammability of these gaseous byproducts. It is worth noting
that the authors also observed similar thermal instability
hazards with NaH/DMAc and NaH/DMSO mixtures.
Despite the numerous reports, including two Organic Process
Research & Development editorials38 intended to caution
scientists, the hazards associated with NaH/DMF reactive
mixtures remain underappreciated, and such mixtures continue
to be used on both laboratory and large scales in the chemistry
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community, as indicated by the continued appearance of large
numbers of articles with NaH/DMF in peer-reviewed journals
each year (Figure 3). For example, Nasipuri et al. employed
Figure 3. Number of publications using NaH/DMF in selected
journals in 2014−2019.
NaH in DMF for the aromatization of various cyclohexenones.
The authors acknowledged the exothermic decomposition of
DMF in the presence of NaH but still carried out their
reactions at 100 °C.39 A large-scale alkylation of 18 with
propargyl bromide (19)40 using 880 moles of NaH (35.2 kg of
60 wt % NaH in mineral oil) and 680 kg of DMF was reported
in 2007 (Scheme 7).41 In this case, the authors recognized the
Scheme 7. Scale-Up of Hazardous NaH/DMF Conditions
for the Synthesis of 20
safety hazards associated with NaH/DMF but stated that
alternative reaction conditions were not available and that all of
the reactions were conducted within safe operating ranges in a
reactor of compatible materials of construction. It needs to be
pointed out that calorimetry studies have proven that these
hazards are independent of the reactor material of
construction. Furthermore, critical reaction parameters such
as residual water, reaction temperature, and relative concen-
tration of NaH do not completely eliminate the thermal
instability hazards associated with NaH/DMF. In the early
2010s, an incident at an undisclosed organization involving the
scale-up of an alkylation reaction using NaH in the presence of
DMF in a 100 L glass reactor resulted in a runaway reaction
and a fire and caused two fatalities.42 These examples highlight
the need for continued education about these safety hazards to
promote awareness in the broader chemistry community and
encourage researchers to identify a safer replacement for NaH/
DMF.
It needs to be pointed out that mixtures of DMF with other
metal hydrides potentially possess similar instability hazards.
For example, DSC evaluation of a mixture of 12.5 mg of
lithium hydride (LiH) and 325 μL of DMF detected an
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exothermic event starting at 188 °C with an energy release of
−632 J/g when the experiment was performed in an
atmosphere of air in the headspace (Table 1, entry 13). It is
worth noting that CaH2 has frequently been used as a drying
agent for the preparation of anhydrous DMF, during which
DMF is distilled over CaH2 at atmospheric or reduced
pressure.43 It is imperative for researchers to understand the
potential hazards associated with mixtures of DMF and metal
hydrides, including CaH2, and to avoid such operations. Other
drying agents suitable for the preparation of anhydrous DMF
include calcium sulfate (CaSO4), magnesium sulfate (MgSO4),
silica gel, and 4 Å molecular sieves.
DMF also decomposes exothermically in the presence of
sodium tert-butoxide (NaOt-Bu) at elevated temperatures.
DSC evaluation of a mixture of 40% NaOt-Bu and 60% DMF
detected an exothermic event starting at 275 °C with a total
energy release of −159 J/g (Table 1, entry 16). In addition,
there was an energy release of −45 J/g when this mixture was
prepared by combining NaOt-Bu with DMF at 25 °C in a μRC
(Table 1, entry 14). Incompatibility of DMF with other bases
such as ammonia was also reported.44
2.3. Potential Safety Hazards of DMF in the Presence
of Halogenated Reagents. The interactions of DMF with
chlorination reagents such as thionyl chloride (SOCl2), oxalyl
chloride, cyanuric chloride, pivaloyl chloride, phosphorus
oxychloride (POCl3), etc. have found broad applications in
synthetic organic chemistry. The key intermediate, namely, the
Vilsmeier−Haack reagent, is formed when DMF is treated with
these chlorination reagents and then further reacts with
alcohols, carboxylic acids, electron-rich aromatics, etc. to
deliver alkyl chloride,45 acid chloride,46 formyl,47 and nitrile48
products (Scheme 8). Among these transformations, only a
Scheme 8. Formation and Application of the Vilsmeier−
Haack Reagent
catalytic amount of DMF is required to effect chlorination of
alcohols and carboxylic acids to afford the corresponding alkyl
chlorides and acid chlorides.
The reactions of DMF with these chlorination reagents are
significantly exothermic. An exotherm of −140 J/g was
observed when a mixture was prepared by combining SOCl2
with DMF at 25 °C in a μRC (Table 1, entry 17). DSC
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Figure 4. DSC profile of a SOCl2/DMF mixture under N2.
evaluation of a 1:1 mixture SOCl2 and DMF under an
atmosphere of N2 in the headspace detected an exothermic
event starting at 111 °C with a total energy release of −488 J/g
(Figure 4 and Table 1, entry 18). Furthermore, non-
condensable gases are formed during the reactions of DMF
with chlorination reagents. More specifically, sulfur dioxide
(SO2) and hydrogen chloride (HCl) are released during the
reaction of DMF with SOCl2, while CO, CO2, and HCl are the
byproducts from the reaction of DMF with oxalyl chloride.49
The formation of these noncondensable gases can cause a
dramatic pressure rise without proper venting as well as a
possible need for scrubbing due to environmental emission
limits, increasing the severity of the hazards. Under certain
conditions, i.e., an “all-in” scenario in which all of the reactants
are accumulated and the reaction is heated at elevated
temperatures, the heat release rate could overwhelm the ability
of the reactors to remove heat from the reaction system and
result in runaway scenarios or even explosions.
A runaway incident involving a DMF/SOCl2 mixture was
reported in 1977 by Spitulnik at Eastman Kodak in a
communication to Chemical & Engineering News.50 It was
found that SOCl2 in DMF provided acceptable results as a
dehydrating agent to convert amides to nitriles. This condition
was successfully developed for the dehydration of a
phthalamide to the corresponding nitrile. During this specific
run that caused the runaway reaction, a total of 82.5 kg of
SOCl2 was slowly added to 135 kg of DMF in a 200 gal
reactor. The temperature during the addition was maintained
below 30 °C, and the material was stored at ambient
temperature overnight for use on the second day. During
storage, the mixture decomposed exothermically and released
gases, causing the pressure disk on the reactor to rupture.
Root-cause investigation indicated that the specific lot of
SOCl2 used in this reaction contained ca. 90 ppm iron and 90
ppm zinc. Small-scale experiments revealed that a SOCl2/DMF
mixture containing 200 ppm iron powder decomposed after 22
h of stirring at ambient temperature, while a control
experiment using freshly distilled SOCl2 in DMF showed
that the mixture was stable for at least 48 h at ambient
temperature. These results indicated that the presence of trace
levels of iron potentially catalyzed the decomposition of the
SOCl2/DMF mixture.
An analogous incident involving SOCl2/DMF was reported
by Joshi in 1986, in which a sudden exotherm and pressure rise
caused by spontaneous decomposition occurred in a 400 L
reactor during vacuum distillation of a SOCl2/DMF mixture to
remove SO2.51 In addition to SO2, sulfur (S), HCl, and N,N-
dimethylcarbamoyl chloride (DMCC), a potent carcinogen52
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that is heavily regulated in many countries with strict site
volume limits, were also identified among the decomposition
products. Thermal stability studies using an adiabatic
calorimeter indicated that a runaway reaction occurred after
8 h at 60 °C, but after only 20 min when the mixture was
maintained at 85 °C. The mixture decomposed much faster
after SO2 was removed. A later communication to Chemical &
Engineering News by Zemlicka indicated that the inherent safety
hazards associated with the SOCl2/DMF mixture could be
circumvented by using phosgene (COCl2) instead of SOCl2.53
The author stated that heating was completely unnecessary and
that the exotherm could be controlled by external cooling.
However, it needs to be pointed out that this approach does
not address the inherent thermal instability hazards associated
with the resulting Vilsmeier−Haack reagent. In addition,
phosgene is highly toxic,54 and thus, it is imperative that a
proper control strategy and adequate protection should be in
place when handling phosgene. Violent decomposition during
distillation to remove SO2 from a SOCl2/DMF mixture was
also reported by Cardillo in 1992.55 In addition, exothermic
decomposition of a SOCl2/DMF mixture was observed during
the chlorination of hexadiyndiol.56
The Vilsmeier−Haack reaction has found wide applications
in chemical industry, including the preparation of pharma-
ceutical ingredients57 and crop protection products. 58
Commercially available Vilsmeier−Haack reagent 21 has
been used in the large-scale preparation of pharmaceutical
ingredients59 However, the potential safety hazards associated
with the Vilsmeier−Haack reaction are well-documented in the
literature. For example, Dyer et al. applied reaction calorimetry
and process modeling to understand the potential safety
hazards associated with the Vilsmeier−Haack formylation of
3,5-dimethoxyphenol (30) in order to ensure rapid and safe
scale-up of this reaction and successfully scaled up this reaction
in a 50 L reactor (Scheme 9).60 However, the potential thermal
instability hazards associated with the Vilsmeier−Haack
reagent were not discussed in that article.
Scheme 9. Vilsmeier−Haack Formylation of 3,5-
Dimethoxyphenol (30)
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Miyake et al. performed reaction calorimetry and thermal titanium cell detected an exothermic event with an onset
stability evaluations of the Vilsmeier−Haack complex.61 RC1 temperature of 35 °C, which resulted in a temperature rise to
analysis of the formation of the Vilsmeier−Haack complex 180 °C. The test was terminated to avoid potential damage to
from POCl3/DMF indicated a reaction enthalpy (ΔH) of −57 the instrument. The cool-down pressure of 77 bar indicated
kJ/mol at temperatures between 15 and 50 °C, while ARC the formation of noncondensable gases during the decom-
evaluation of a 1:6 POCl3/DMF mixture revealed two position. The maximum temperature and pressure rise rates for
exothermic decomposition events at ca. 120 and ca. 180 °C. this decomposition were 8 °C/min and 18 bar/min,
In addition, the researchers also studied the influence of respectively.
solvent and temperature on the thermal stability of the It is worth noting that the researchers noticed incon-
Vilsmeier−Haack complex. On the basis of the RC1 and ARC sistencies between the ARC data and their practical
results, the authors concluded that the thermal instability of observations and investigated the compatibility between the
the Vilsmeier−Haack complex was the major safety hazard of reaction mixtures and the material of construction of the ARC
their specific process, which could potentially lead to runaway cells. The thermal decomposition behaviors were found to be
scenarios. The reaction in N-methylformamide (MFA) as the consistent when the reaction was tested in Hastelloy and glass
solvent was deemed to be safer on the basis that the heat cells. In both cases, the onset temperature of the exotherm (85
release during generation of the Vilsmeier−Haack complex in or 93 °C, respectively) was significantly higher than that when
MFA was about half of that in DMF, while the thermal stability the titanium cell was used (35 °C). The maximum temperature
profile of the formed Vilsmeier−Haack complex in MFA was and pressure rise rates were much lower than those in titanium
similar to that in DMF. cell, indicating potential reactions between the reaction
Bollyn at Agfa-Gevaert reported a thorough risk assessment mixtures and titanium ARC cells (Table 2). These results
of two potential processes for the Vilsmeier−Haack
formylation of N,N-dimethylaniline (Scheme 10).62 For the Table 2. ARC Evaluation of Postreaction Mixtures of the
Vilsmeier−Haack Reagent with N,N-Dimethylaniline by
Scheme 10. Vilsmeier−Haack Formylation of N,N- Bollyn
Dimethylaniline (32)
two-stage
process one-pot process
titanium Hastelloy glass
parameter titanium cell cell cell cell
onset temp. (°C) 48 35 85 93
T @ max rate (°C) 238 150 121 94
max T rate 4.6 8 0.1 0.08
(°C/min)
max P rate 4.2 18 0.2 0.29
two-stage DMF process, in which the Vilsmeier−Haack (bar/min)
reagent was formed and then allowed to react with N,N- TD24 (°C)a 30 31 90 77
a
dimethylaniline (32), a reaction calorimetry study by RC1 TD24 is the temperature with a time to maximum rate of 24 h.
revealed ΔH values of −46 kJ/mol (including ca. −10 kJ/mol
from the interaction with residual water) for the formation of highlight the importance of using compatible test cells (i.e.,
the Vilsmeier−Haack reagent from POCl3/DMF and −107 kJ/ DSC crucibles and ARC cells) to avoid undesired reactions
mol for the reaction of the Vilsmeier−Haack reagent with 32. between the test samples and the test cells during thermal
A thermal stability evaluation of the formed Vilsmeier−Haack hazard evaluations.
reagent mixture by ARC detected an exothermic decom- Exothermic behavior of a mixture of chlorine (Cl2) and
position with an onset temperature of 67 °C (corrected for the DMF was first reported in 1952 by Adams and Braun, who
phi factor), which resulted in drastic temperature and pressure were attempting to chlorinate a benzenesulfonyl derivative of
increases starting at ca. 140 °C. This exotherm, with a aromatic amine 34 (Scheme 11) with Cl2 in DMF.63 The
maximum temperature rise rate of 28 °C/min and a maximum
pressure rise rate of 48 bar/min, was determined to be Scheme 11. Chlorination of a Benzenesulfonyl Derivative of
comparable to an explosion scenario. ARC analysis of the final Aromatic Amine 34 with Cl2 in DMF
reaction mixture after the reaction of the Vilsmeier−Haack
reagent with 32 detected an exotherm with an onset
temperature of 48 °C and maximum temperature and pressure
rise rates of 4.6 °C/min and 4.2 bar/min, respectively. The test
was terminated because the cutoff temperature of 300 °C was
reached, at which point the pressure was 77 bar. The material
of construction of the ARC cells used in these experiments was
not specified in the article but was presumably titanium on the
basis of the discussion. For the one-pot DMF process, in which researchers noticed that DMF underwent chlorination in the
POCl3 was added to a solution of 32 in DMF at the desired presence of Cl2, resulting in an exothermic reaction. The
process temperature, RC1 analysis indicated a ΔH of −142 kJ/ reaction temperature was maintained under 60 °C through
mol, comparable to that of the two-stage process. RC1 regulation of the Cl2 flow.
evaluation of the reaction heat profile at different temperatures After a runaway reaction occurred (details of that incident
showed that the ΔH values were comparable at 15, 25, and 40 were not disclosed), Woltornist realized that the potential
°C. ARC evaluation of the postreaction mixture using a safety hazards associated with chlorination using Cl2 in DMF
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Organic Process Research & Development
were not fully recognized and performed a series of studies to
understand the hazards.64 When dry Cl2 was sparged at a fixed
feed rate into dry DMF in a 250 mL unjacketed three-neck
round-bottom flask, an initial exotherm caused by dissolution
of Cl2 was observed, followed by a significant exothermic
reaction leading to eruption after the solution reached
saturation. In a separate experiment, a violent reaction and
rapid gas evolution were observed several minutes after a
saturated solution of Cl2 in DMF was placed in an adiabatic
Dewar at 15 °C. N,N,N′,N′-Tetramethylformamidinium
chloride, dimethylamine hydrochloride (Me2NH·HCl), CO2,
and CO were identified among the decomposition products.
It needs to be pointed out that mixtures of other halogen
elements and DMF also possess similar hazards. For example, a
mixture of Br2 and DMF decomposed explosively in an
autoclave when the mixture temperature and pressure
exceeded 100 °C and 135 bar, respectively, triggering the
rupture disc.65 Many products, including N-bromodimethyl-
amine, CO, and hydrogen bromide (HBr), were suspected to
be formed during the decomposition. Similarly, fluorine (F2)
can also react with DMF to cause violent decomposition of
DMF and result in potential runaway reactions or even
explosions.66 The incompatibility of halogen elements with
DMF could also be potentially caused by their oxidizing ability
(see section 2.4).
N-Halosuccinimides in DMF have been used for halogen-
ation reactions67 as well as for oxidation of alcohols. For
example, recently Kulkarni et al. developed mild oxidation
conditions for the conversion of benzylic alcohols 36 to the
corresponding aldehydes and ketones 37 using N-chlorosucci-
nimide (NCS)/DMF (Scheme 12).68 This method was
demonstrated to give easy access to a wide variety of carbonyl
compounds in good yields under metal-free conditions without
the use of corrosive reagents.
Scheme 12. Oxidation of Benzylic Alcohols to Aldehydes
and Ketones Using NCS/DMF
The potential safety hazards associated with mixtures of N-
halosuccinimides and DMF have been a concern in the
chemistry community. In a recent study, Shimizu et al.
evaluated the incompatibilities between N-bromosuccinimide
(NBS) and a variety of solvents.69 RC1e evaluation of 10 wt %
NBS in DMF at 80 °C indicated a heat generation of −129 kJ/
mol, resulting in a ΔTad of ca. 33 °C. ARSST analysis of 10 wt
% NBS in DMF revealed an exothermic decomposition with an
onset temperature of 108 °C and a maximum temperature rise
rate of 105 °C/min. The onset temperature remained the same
when 30 wt % NBS in DMF was evaluated, but with a ΔTad of
ca. 100 °C. Similarly, RC1e evaluation of a 10 wt % solution of
1,3-dibromo-5,5-dimethylhydantoin (DBDMH) in DMF at 60
°C indicated a heat release of −265 kJ/mol with a ΔTad of ca.
49 °C and a maximum temperature rise rate of 78 °C/min, and
ARSST analysis revealed an exothermic decomposition event
with an onset temperature of 99 °C and a ΔTad of ca. 26 °C. It
is worth noting that similar thermal behaviors were observed
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with NBS/DMAc and DBDMH/DMAc mixtures. The authors
concluded that these results showed the behavior of
autocatalytic heat generation, and strict temperature control
was necessary to avoid potential incidents associated with the
mixtures of NBS and DBDMH with amides. ARC evaluation of
a 2.15 g sample of a mixture consisting of 12.6% NBS and
87.4% DMF (phi = 3.16) also showed an exothermic event
starting at 61 °C with a total energy release of −126 J/g (Table
1, entry 19).
Other halogenated reagents, such as acyl halides (e.g.,
cyanuric chloride70 and trichloroisocyanuric acid71), alkyl
halides (i.e., carbon tetrachloride72 and 1,2,3,4,5,6-hexachlor-
ocyclohexane73), cesium fluoroxysulfate (CsSO4F),74 etc. have
also been reported to undergo very exothermic reactions with
DMF, which may be violent enough under certain conditions
to cause potential runaway scenarios or even explosions.
2.4. Potential Safety Hazards of DMF in the Presence
of Oxidants. Studies have shown that DMF is not an inert
solvent in the presence of oxidants75 and could result in violent
reactions or even explosions with strong oxidants. DSC
evaluation of DMF under an atmosphere of air in the
headspace detected an exothermic event with an onset
temperature of 170 °C and a total energy release of −109 J/
g (Table 1, entry 2), whereas DMF was found to be stable at
temperatures of >400 °C when evaluated under an atmosphere
of N2. This exothermic event is suspected to be caused by the
oxidation of DMF by oxygen (O2) in the air headspace. DMF
has frequently been used in a variety of oxidation reactions
because of its desirable physical properties that allow it to
solubilize both organic and inorganic compounds.76 For
example, DMF was employed as a solvent in the Corey−
Schmidt oxidation of primary alcohols using pyridinium
dichromate (PDC).77 Interestingly, DMF was found to
enhance the oxidation to the corresponding carboxylic acids,
while aldehydes and ketones were formed as the major
products when dichloromethane (DCM) was used as the
solvent.
Over the years, many incidents associated with the
incompatibility of DMF with oxidants have been reported.
For example, an incident associated with the interaction of
DMF with chromium trioxide (CrO3) was reported in 1970 by
Neumann in a note to Chemical & Engineering News.78 The
researcher was attempting to repeat a procedure reported by
Snatzke for the oxidation of a secondary alcohol to the
corresponding ketone.79 A flame suddenly flashed from the
surface of the DMF solution and sprayed the solution all over
the inside of the hood when CrO3 was added to the reaction
mixture. A similar observation was reported in 1981 by
Heathcock at the University of California, Berkeley,80 who
noted “an almost instantaneous inflammation, followed by an
eruption which forcibly ejected the contents from the flask
onto the inner walls of the fume hood” during the preparation
of a 10 wt % solution of CrO3 in DMF by addition of 2 g of
CrO3 to 18 mL of DMF.
Potassium permanganate (KMnO4) also reacts violently
with DMF. A significant instantaneous energy release of −820
J/g was observed when KMnO4 was combined with DMF at
36 °C in a μRC (Table 1, entry 20). In addition, DSC
evaluation of a mixture of 11 mg of KMnO4 and 11.6 μL of
DMF showed two exothermic events starting at 60 and 208 °C.
The energy outputs for these two events were −71 and −193
J/g, respectively (Table 1, entries 21 and 22). The potential
hazards associated with the incompatibility of DMF with
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Scheme 13. Synthesis of the Insecticidal Candidate Tyclopyrazoflor
KMnO4 were first reported by Brain et al. in 1976 in a paper
describing the synthesis of antibacterial compounds based on
1,2-secopenicillins, in which the authors cautioned that solid
KMnO4 should not be added to neat DMF because a violent
exothermic reaction would occur.81 A laboratory explosion
involving KMnO4 and DMF was reported in 1980 in a
communication to Chemical & Engineering News by Finlay at E.
I. du Pont de Nemours & Co.82 This incident occurred when
20 g of KMnO4 was mixed with 100 g of DMF, which
shattered the reaction bottle and nearby bottles and sprayed
the contents and broken glass pieces throughout the
laboratory. Small-scale trials with 1 g of KMnO4 and 5 g of
DMF resulted in a rapid temperature rise after stirring for 3−4
min, with popping noises and fume evolution. The author
noted that KMnO4 appeared to be reduced to MnO2.
Shortly after the incident report by Finlay, Thomas
reiterated the potential explosion hazards associated with
DMF and strong oxidizing agents such as KMnO4 and CrO3
and warned that the use of these mixtures should be treated
with caution.83 Many communications appeared in Chemical &
Engineering News in 1981 discussing the importance of mixing
order and time to mitigate the potential explosion hazards
associated with the mixtures of DMF and strong oxidants.84
However, it is important for scientists to recognize that
although a judicious choice of the mixing order and time may
provide a way to control the exotherm of mixing from the
reaction of DMF and strong oxidants, it does not completely
eliminate the inherent explosion hazards associated with the
incompatibility of DMF with oxidants. It is also worth noting
that because the oxidative power of the oxidants is reduced by
DMF, the oxidants may lose the desired oxidizing ability in
DMF solutions.
m-Chloroperoxybenzoic acid (m-CPBA) has been widely
used to effect a variety of oxidation transformations on scale.85
The potential safety hazards associated with its inherent shock
sensitivity, explosive thermal decomposition, and incompati-
bility with a variety of substances are well-known.86 Kubota
and Takeuchi at Fujisawa Pharmaceuticals Co. Ltd. reported
an explosion involving a mixture of DMF with m-CPBA.87 The
authors noted that different research groups had conducted
oxidative transformations using m-CPBA in DMF without an
incident previously.88 In this particular case, the researchers
were oxidizing a certain sulfide to the corresponding sulfoxide
on the pilot scale using 11.0 kg of m-CPBA and 6.3 kg of DMF.
They observed a small amount of insoluble solids after m-
CPBA and DMF were mixed, which was filtered off, and the
filtrate was slowly added to the reaction mixture. The
temperature of the m-CPBA/DMF mixture suddenly rose,
causing gas evolution and an explosion shortly after. ARC
evaluation of a mixture of m-CPBA and DMF showed that the
contents slowly decomposed exothermically from ca. 26 to ca.
70 °C over 185 min, which was immediately followed by an
explosive decomposition to ca. 200 °C and evolution of white
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smoke. Further root-cause investigation revealed that m-
chlorobenzoyl peroxide (m-CBPO) was formed over time
during storage of the m-CPBA solution in DMF, which also
showed explosive decomposition starting at low temperatures
during thermal stability evaluation. The authors thus
concluded that the explosion was caused by the explosive
decomposition of m-CBPO that was formed in the
concentrated m-CPBA/DMF mixture at elevated temperature.
However, the data presented in that contribution did not
completely rule out the possibility that m-CPBA at least
partially contributed to the explosion.
It needs to be pointed out that the inherent instability of m-
CPBA and the incompatibility of m-CPBA with DMF should
be recognized and treated with caution regardless of the
presence of m-CBPO. Although the authors noted that an
improved process using DCM as an alternative solvent was
successfully scaled up, no details of their safety evaluation of
the m-CPBA/DCM solution was provided in that paper. As
discussed below, DCM should not be viewed as an inherently
safer solvent for oxidations involving m-CPBA.
Zhang et al. performed a thorough evaluation of the thermal
stability of m-CPBA in a variety of solvents.89 Their studies
indicated that a solution of m-CPBA in DCM is not inherently
safer, with an onset temperature of 56 °C and a heat release of
−417 J/g of mixture (normalized to −919 J/g of m-CPBA)
when a mixture of 1.1 g of m-CPBA and 1 mL of DCM was
evaluated by RADEX. Not surprisingly, their study showed that
a solution of 1.1 g of m-CPBA in 1 mL of DMF was detected
to degrade at 46 °C with an energy release of −562 J/g of
mixture (normalized to −1045 J/g of m-CPBA). It is worth
noting that similar exothermic behavior was observed by
RADEX for a solution of 1.1 g of m-CPBA in 1 mL of DMAc,
with a decomposition onset temperature of 42 °C and a total
energy release of −545 J/g of mixture (normalized to −1009 J/
g of m-CPBA). These results indicate that DMAc is not a safer
replacement for DMF. The researchers further evaluated the
impact of concentration, addition sequence, and operating
temperature on the thermal profile of m-CPBA/DMF mixtures
and identified the following measures to ensure safer
operations of their specific process:
• controlling the concentration of m-CPBA in DMF below
0.13 g/mL;
• ensuring the correct addition order, namely, precooling
DMF and then adding m-CPBA to DMF;
• maintaining the internal temperature below 10 °C
during the addition of m-CPBA to DMF;
• using the m-CPBA/DMF solution immediately after
preparation.
The authors warned that these safety measures “are intended
to raise awareness of the topic in the community only and
cannot guarantee safe operating conditions under all possible
circumstances”. Researchers should conduct thorough safety
hazard evaluations when DMF is involved with strong oxidants
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Organic Process Research & Development
Scheme 14. Decomposition of DMF in the Presence of NaBH4
in chemical reactions and design proper control strategies to
mitigate inherent explosion hazards.
An uncontrollable exotherm in a small-scale oxidation using
sodium persulfate (Na2S2O8) in DMF was observed by Yang et
al. at Corteva Agriscience during the development of an
insecticidal candidate, tyclopyrazoflor (40) (Scheme 13).90
Although the desired product 39 was observed when
dihydropyrazole 38 was treated with Na2S2O8 in DMF at 80
°C, it was isolated in low yields of < 30% with many impurities.
The reaction was incomplete even with an excess amount of
Na2S2O8, presumably caused by the decomposition of Na2S2O8
in DMF. After optimization, the researchers were able to
identify safer and greener alternative conditions to effect this
oxidation reaction, namely, the use of potassium ferricyanide
(K3FeCN6) in the presence of aqueous KOH at 70−90 °C,
which afforded a cleaner reaction profile and a higher isolated
yield.91
Other oxidants such as perchlorates {i.e., sodium perchlorate
(NaClO4),92 titanium tetraperchlorate [Ti(ClO4)4],93 etc.},
nitrates94 {i.e., magnesium nitrate [Mg(NO3)2],95 alkyl
nitrates,96 etc.}, and SO3 have also been reported to cause
potential safety hazards when in contact with DMF. It has been
reported that a bottle of the SO3−DMF complex exploded
during storage.26 Although it was suspected that SO3 reacted
with moisture to form sulfuric acid (H2SO4) that subsequently
hydrolyzed DMF to release CO and other decomposition
products (see section 2.1), this explosion could also have been
caused by the oxidizing ability of SO3 and/or H2SO4.
2.5. Potential Safety Hazards of DMF in the Presence
of Reductants. DMF has also been frequently used as a
solvent in reduction transformations [i.e., using sodium
borohydride (NaBH4)]97 because of its desirable physical
properties that allow it to solubilize both organic and inorganic
compounds. However, similar to other amides, DMF can be
readily reduced to trimethylamine (Me3N) by certain reducing
agents, which could be violent and potentially lead to runway
reactions or even explosions when strong reductants are
employed. For example, Corey and Block reported that
Paquette communicated a serious explosion during the large-
scale borohydride reduction of 2,5-bis(endo-dichloro)-7-
thiabicyclo[2.2.1]heptane in DMF.98 An explosion involving
the use of NaBH4 in DMF was reported in a communication to
Chemical & Engineering News by Yeowell et al. in 1979,99 in
which a violent explosion of a saturated solution of 13 kg of
NaBH4 in 70 kg of DMF at 17 °C occurred at a plant and
caused a spontaneous ignition of flammable gases released
from the explosion. The researchers performed a root-cause
investigation on a small scale using 3 g of NaBH4 in 17 mL of
DMF and discovered that a runaway reaction would occur after
a certain temperature-dependent induction period. In this
small-scale case, the induction period ranged from 45 min at
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90 °C to 45 h at 62 °C. It was noticed that the thermometer
placed in the solid residue indicated a sudden temperature
spike to 310 °C from 190 °C right after the runaway reaction.
Me3N was determined to be the major component of the
flammable gas released from the reaction, along with trace
amounts of H2 and Me2NH. Ganem and Osby100 also
cautioned the chemistry community that “Concentrated
solutions of NaBH4 in DMF in the absence of reducible
substrate are unsafe at elevated temperatures. Violent
exothermic reactions can occur, generating flammable gases.
Dissolving NaBH4 in DMF on a large scale with inefficient
cooling is hazardous.”
Liu and Schwartz studied the interaction of NaBH4 with
DMF and observed that the presence of certain metal
complexes such as bis(cyclopentadienyl)titanium(IV) dichlor-
ide (Cp2TiCl2) or lithium chloride (LiCl) could significantly
shorten the induction period for the reduction of DMF,
releasing Me3N as the major product.101 It was noticed that the
addition of 20 mol % LiCl (relative to the amount of NaBH4)
to a mixture of 30 mmol of NaBH4 in 30 mL of DMF
significantly shortened the reduction induction time from >2 h
to 1 h at 95 °C. Similarly, adding 2 mol % Cp2TiCl2 to a
mixture of 30 mmol of NaBH4 in 30 mL of DMF reduced the
induction time to 30 min, while an induction period of 50 min
was observed when the amount of Cp2TiCl2 was further
reduced to 1 mol %. The reaction occurred spontaneously
when 1 equiv of LiCl was added to a mixture of 30 mmol of
NaBH4 and 1 mol % Cp2TiCl2 in 30 mL of DMF. In addition
to Me3N, bis(dimethylamino)methane was also observed
during this reaction. The authors proposed that the
intermediate Na+BH3(OCH2NMe2)− was formed in the initial
step and then further reacted to afford Me3N and bis-
(dimethylamino)methane (Scheme 14).102
Shimizu et al. at Shionogi & Co., Ltd. performed a thorough
thermal stability evaluation of solutions of NaBH4 in DMF and
DMAc.103 DSC analysis indicated that the presence of certain
additives such as water, MeOH, HCO2H, and iron rust affected
the onset temperature of DMF decomposition as well as the
total released energy (Table 3). ARC analysis of a NaBH4/
DMF mixture (15.7 wt % solution) detected an exothermic
decomposition event with an onset temperature of 95 °C. The
maximum temperature rise rate was 547 °C/min at 137 °C. In
contrast, ARC evaluation of a NaBH4/DMAc mixture (11.7 wt
% solution) detected an exothermic decomposition event with
an onset temperature of 125 °C. The maximum temperature
rise rate was 79 °C/min at 183 °C. The authors concluded that
the decomposition onset temperature of NaBH4 in DMF was
ca. 30 °C lower than that in DMAc. The presence of HCO2H
contamination affected the decomposition onset temperature
more severely in DMF than in DMAc, and the rate of adiabatic
decomposition of NaBH4 in DMF was faster than that in
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Table 3. DSC Evaluation of the Thermal Stability of For safe scale-up, understanding the thermal profile is
NaBH4/DMF and NaBH4/DMAc Mixtures by Shimizu et al. important, especially when reactive mixtures could overwhelm
the ability of the cooling system to remove heat from the
solvent additive (wt %) onset temp. (°C) energy release (J/g)
reaction system under batch operations. If indeed this type of
DMF − 189 −757
reaction has to be carried out, appropriate emergency vent
H2O (0.51) 186 −827
MeOH (0.46) 182 −634
sizing should be assessed to ensure that the safety valve or
HCO2H (0.45) 175 −662
rupture disk is properly designed to protect the vessel from
HCO2H (3.64) 152 −604 potential thermal runaway. It is important to avoid large
iron rust (0.83) 189 −751 excesses of DMF when it is used as a reagent or a catalyst. It is
DMAc − 216 −573 imperative for researchers to conduct thorough process safety
H2O (0.38) 218 −559 evaluations when DMF is involved in a chemical reaction and
MeOH (0.60) 215 −603 to design proper control strategies to mitigate these inherent
HCO2H (0.39) 201 −515 safety risks during research and scale-up.

HCO2H (3.43) 196 −506
iron rust (0.40) 218 −533
DMAc. On the basis of these results, the researchers decided to
carry out the reduction reaction in DMAc and were able to
safely handle a solution of 11.7 kg of NaBH4 in 88 kg of DMAc
to reduce an ester in the plant.
Precautions should also be taken when DMF is mixed with
other reductants such as alkaline metals (i.e., sodium,104
potassium) and borane and its complexes that typically effect
reduction of amides. NaH has also been used as a reductant,105
and the potential explosion hazards associated with its mixtures
with DMF are discussed in section 2.2.
2.6. Potential Safety Hazards of DMF in the Presence
of Other Substances. As discussed throughout this review,
DMF is not an inert solvent, and any substances that react with
typical amide and/or formyl functional groups could
potentially trigger exothermic decomposition of DMF and
result in potential runaway scenarios and even explosions. For
example, methylene diisocyanate,106 triethylaluminum,107
potassium methylselenide,108 and phosphorus pentoxide
(P4O10)109 have also been reported to react exothermically
with DMF. The reactions of these reagents with DMF may be
violent under certain conditions and lead to potential runaway
scenarios or even explosions. It is thus imperative for scientists
to perform thorough thermal hazard evaluations whenever
DMF is used in a chemical reaction to understand the potential
safety hazards and design proper control strategies to mitigate
these inherent safety risks.
3. CONCLUSIONS
DMF is one of the preferred polar aprotic solvents for a variety
■
EXPERIMENTAL SECTION
General. All of the reagents were commercially available
and used as purchased without further purification. Unless
otherwise noted, all of the experiments were conducted under
an atmosphere of N2 in the headspace for DSC and ARC
evaluations.
HOM Analysis. A μRC manufactured by Thermal Hazard
Technology was used for HOM experiments in this study. One
reaction component was sealed in a 2 mL glass vial with a
magnetic stir bar, and the system was adjusted to the desired
temperature. A second reaction component was loaded via a
syringe, and the heat flow to/from the mixture and the
pressure generated were measured.
DSC Analysis. A Q2500 DSC from TA Instruments was
used for the constant-heating-rate tests in this study. A sample
was sealed within a gold-plated high-pressure crucible or a glass
capillary. The sealed crucible had a total internal volume of ca.
20 μL and was able to withstand pressures of up to 3000 psi at
400 °C, preventing the release of any reaction materials,
products, or byproducts.110 Unless otherwise noted, all of the
evaluations were performed with a temperature ramp rate of 10
°C/min.
ARC Analysis. An ARC manufactured by Thermal Hazard
Technology was used in this study. A specified amount of
sample was loaded into a standard Hastelloy C ARC cell with
nitrogen in the headspace. The ARC experiment was
performed in heat−wait−search mode with a detection
threshold of 0.02 °C/min.111 Data collected in our laboratory
were not corrected for the phi factor.

of chemical reactions because of its desirable physical
properties that allow it to solubilize both organic and inorganic
compounds. In addition, DMF has found broad application in
a wide variety of chemical transformations over the years.
However, DMF is not an inert solvent toward certain
substances, and numerous incidents have occurred over the
years. As summarized throughout this review, the substances
causing detrimental effects on the potential safety hazards
associated with DMF can be categorized as acids, bases,
halogenated reagents, oxidants, and reductants. It should be
noted that in some cases exothermic events have occurred even
after extended additions to control the reaction temperature;
thus, while a judicious choice of the mixing order and time may
allow for initial temperature control, these considerations may
not eliminate any inherent hazard. Other substances not
discussed in this review may also induce the decomposition of
DMF to magnify the associated hazards.
1596
■
AUTHOR INFORMATION
Corresponding Author
Qiang Yang − Product & Process Technology R&D, Corteva
Agriscience, Indianapolis, Indiana 46268, United States;
orcid.org/0000-0003-3762-5015; Email: qiang.yang@
corteva.com
Authors
Min Sheng − Reactive Chemicals, Product & Process Technology
R&D, Corteva Agriscience, Midland, Michigan 48667, United
States
Yongliang Huang − Product & Process Technology R&D,
Corteva Agriscience, Shanghai 201203, China
Complete contact information is available at:
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Org. Process Res. Dev. 2020, 24, 1586−1601
Organic Process Research & Development
Author Contributions
The manuscript was written through contributions of all
authors. All of the authors approved the final version of the
manuscript.
Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS
The authors thank the Reactive Chemicals Group of their
heritage company, the Dow Chemical Company, for sharing
testing methodologies and historical data.
■ REFERENCES
(1) (a) Marsella, J. A. Dimethylformamide. In Kirk-Othmer
Encyclopedia of Chemical Technology, January 18, 2013. https://
onlinelibrary.wiley.com/doi/10.1002/0471238961.
0409130513011819.a01.pub2 (accessed 2020-05-23). (b) Long, G.;
Meek, M. E.; Lewis, M. Concise International Chemical Assessment
Document 31: N,N-Dimethylformamide. World Health Organization,
2001. https://www.who.int/ipcs/publications/cicad/en/cicad31.
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