Case Studies in Process Safety:
Ensuring the Basis of Safety
Throughout the Development Process
Susan Shilcrat
Process Safety WW
GlaxoSmithKline Pharmaceuticals
Organic Process Research & Development
21 March 2012; San Francisco
Process Safety Adjusting to New Environment
How can we use the safety test to obtain the maximum amount of
information with the least amount of effort to improve our success in
scale-up?
Shorter timelines
 Same standard for the basis of safety
Less resource of time and manpower
Consideration of scale
Consideration of goals
“Nice-to-haves” later in
development
Case Studies from the Trenches
Investigation of an industrial incident
N-Halo imide chemistry – achieving a basis of safety
despite inherent incompatibilities
Investigation of a laboratory runaway
Hazards of DMSO chemistry
Investigation of an Industrial
Process Safety Incident
Iodination Incident in Manufacturing
I
COOH
H 3C
X
Unsaturated Acid
+
I2
Y
Iodine
H 3C
COOH
X
I
Y
Halogenated Component
Iodination of unsaturated fatty acid in manufacturing facility
Relatively small scale process run only several times/year (160 kg)
Dedicated vessel
• Acid is preheated to 60 °C using jacket
steam
• Open manway charge of iodine
• Questionable physical state of iodine
• Exothermic reaction on iodine dissolution
• When the operator finished adding the
iodine and tried to close manway port →
• Violent ejection of material, ‘like a volcano’
ensued
• Iodine vapors were all over the
manufacturing and packaging area.
Reactor After Incident
•
•
•
•
•
No personnel were injured
Plant was evacuated
Production halted until investigation
was complete
Current stockpile of material ~ 2-3 months
• Investigation showed mis-calibration of a key thermocouple
• Operator added the iodine when temperature indicator was at 60 °C
However the real temperature was 77 °C
Original Process Safety Hypothesis
By adding the iodine to the unsaturated acid at an elevated
temperature (77 ºC vs. 60-65 ºC), the reaction mixture reached an
unusually high process temperature.
– At this elevated temperature, decomposition of the iodine/fatty acid
mixture initiated, generating more heat and gaseous by-products.
– Unable to close manway due to pressurization.
Uncontrolled temperature rise + rapid gas evolution led to a thermal
runaway reaction, with material violently ejected from the vessel.
Possibility that the process was always on
the borderline of process safety incident
Characterize typical reaction and model
possible runaway scenarios.
.
Initial Investigation
Authentic manufacturing samples were not quickly available
– Worked with available chemical supplies
Unprocessed halogenated material was not available; only diluted,
formulated commercial product.
Unfortunately, an authentic sample of the material ejected from the
vessel had not been saved.
DSC of reaction components showed no areas of concern.
Isothermal Reaction Calorimetry via RC1
Rate of Heat Output (W/kg Acid)
120
100
Heat Output if
Run at 72 oC
80
60
40
Began with isothermal experiments to
simulate actual and mal-op processes:
93-103 kJ/kg acid
patr 45-47 °C
No gas
Mild process without obvious concerns
20
Heat Output if
Run at 60 oC
0
Iodine Addition
-20
0
1
2
3
Time (h)
4
5
6
Thermal Stability on Material from Isothermal
Experiments (ARC)
275
7
250
6
225
5
175
150
4
125
100
3
75
50
2
25
0
1
0
400
800
1200
Time (min)
Mild exotherm initiates ~ 205 – 210 °C
Moderate pressure rise above 175 °C
1600
2000
Pressure (bar)
Temperature (oC)
200
Iodine + Unsaturated Acid: Thermal Stability
A mixture of iodine and unsaturated acid was tested for thermal stability under
10
adiabatic conditions. 275
250
9
225
200
7
175
6
150
5
Pressure
125
4
100
Pressure (bara)
Temperature (oC)
8
Temperature
3
75
2
50
25
1
0
5
10
15
20
25
30
35
40
45
50
55
Time (h)
No significant pressure generation until temperatures > 140 ºC.
Several small exothermic events with low self-heating rates each with a
temperature rise of 5-10 ºC
Results are independent of material source (Aldrich versus Manufacturing
site).
.
275
10
250
9
225
8
200
7
175
6
Temp Hast.
150
5
125
4
Pressure (bar)
Temperature (oC)
Possible Metal Contaminants
Adiabatic experiments on
the acid + iodine using
hastelloy and stainless
steel test bombs.
Pressure Hast
100
3
Temp SS
75
2
Pressure SS
50
1
25
0
0
5
10
15
20
25
30
35
40
45
50
55
60
Time (h)
The onset of exothermic activity appears somewhat earlier in stainless steel bombs (90
ºC versus 105 ºC).
A rise in pressure also appears somewhat earlier and more rapidly in stainless steel
over hastelloy. However, the rate of temperature and pressure rise (max. 0.037 ºC/min
and 0.06 bar/min) are not such to cause a rapid ejection of material as seen on site.
Iodine + Acid: Reaction Calorimetry on Simulated
Incident
150
120
Temp
100
Conv
110
80
90
70
60
50
Heat
30
40
Iodine
Addition
10
20
-10
0
Reaction Temperature (oC) or Thermal
Conversion (%)
Rate of Heat Output (W/kg Oleic Acid)
130
• Iodine was added to the
acid at 77 ºC in a single
portion.
• After 20 min, the jacket
temperature was rapidly
raised to 110 ºC to
simulate the ingress of
steam
-30
-50
-20
0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
1.8
2
Time (h)
The addition of iodine initiated an immediate heat maximum (132 W/kg), tapering down
over 30 min.
Raising the jacket temperature accelerated the rate of heat output, reaching a second
maximum at 105 ºC (142 W/kg).
– Heat output diminished to zero over 1 h.
The overall heat of this operation was 124 kJ/kg starting acid with the capacity to raise
the reaction temperature rise 49 ºC.
No gas output was observed.
Water Contamination?
• Process is run in a dedicated vessel cleaned with City water.
• ArSST test data of unsaturated acid, iodine and water to examine whether
the possible presence of cleaning water catalyzed a decomposition reaction.
Observations
Under several experimental regimes, no evidence of significant or rapid gas
generation was observed until process temperatures > 150 ºC.
– The difficulty in closing the manway is not readily explained by
pressurization caused by gas generation.
The total enthalpy of this process is in the range 93-124 kJ/kg unsaturated
acid with the potential to raise the process temperature 45-49 ºC.
– Therefore even operating at a higher starting temperature, the maximum
achievable reaction temperature should be no greater than 121 ºC.
This is below the temperature that pressurization was observed.
Mixtures of unsaturated acid + iodine prepared according to the reaction
conditions do not show early onset (< 150 ºC) of decomposition.
Heating unsaturated acid + iodine under adiabatic conditions shows low rates
of exothermic activity and pressure increase which are not consistent with a
runaway chemical reaction.
Conclusions
Following our initial investigations, the loss of containment on site
does not appear to be due to a runaway chemical decomposition
caused by the inherent thermal instability of the reaction mixture near
the operating temperatures.
– Process is safe under ordinary operating conditions.
– Production can continue on schedule.
Other Possible Explanations for Incident:
The presence of an unknown contaminant(s) may have catalyzed a
decomposition process at a lower temperature, leading to a runaway.
– Must consider possible contaminants.
Starting temperature was actually > 77 ºC.
– Gross over-heating scenarios were not investigated.
N-Halo Imide Chemistry –
Achieving a Basis Of Safety
Despite Inherent Incompatibilities
NCS Chlorination: Initial Campaign
Halogenation via an N-halo imide (NBS or NCS) can have safety concerns:

Control of a batch reaction

Possible intense heat spikes due to rapid reaction
Examination of this chemistry showed several significant issues:

Additional NCS (2x) was needed to push the reaction to completion

Heat output showed induction period and appeared autocatalytic

Total heat output could bring the reaction to vigorous reflux

Intense heat spikes were observed which would not be adequately controlled on
scale, leading to possible:

Condenser flooding

Reactor pressurization

Loss of containment
Further Process Development
3000
70
65
2500
Temperature
2250
60
2000
Heat: Impure
Rxn Mixture
55
1750
1500
50
1250
45
1000
750
40
500
Heat: Clean Rxn Mix
35
250
0
Reaction Temperature (oC)
Rate of Heat Output (W/kg)
2750
On development, the unfavourable
safety profile was attributed to
byproducts from the previous stage
By-products not fully characterized /
quantitated by existing analytical
methods
30
25
35
45
55
65
75
85
95
Time (min)
By-products chlorinated preferentially to starting material
 Secondary reaction contributed to large ΔHrxn
 Autocatalytic behaviour possibly due to impurity mixture
 No basis of safety without use-test of authentic input material
Total Heat
Maximum Heat Rate
Adiabatic Temperature Rise
Impure Starting
Material
Use-Test Starting
Material
1470 kJ/kg
366 kJ/kg
2965 W/kg
175 W/kg
200 W/L
18 W/L
60 ⁰C
22 ⁰C
Next Campaign – Process Changes
Chemistry developments in previous stage
Changes in order of transformations
– Fewer by-products transferred to chlorination
R’ changes slightly
Changes in solubility necessitate solvent change
Tetrahydrofuran instead of isopropyl acetate
Excess NCS
Safety Test of NCS Chlorination in THF
120
Heat
Heat-up & 3 h hold at 60 °C – thermoneutral;
IPM very little reaction → Heat to 65 °C
Once the reaction mixture was slightly above 60° C
The reaction initiated and an intense heat spike was observed.
patr = 66 ºC
Possibility of loss of containment
Heat output (W/kg)
2000
1500
100
80
Conv
60
Temp
1000
40
500
20
0
0
0
1
2
3
Time (hr)
4
5
Thermal Conversion (%) or Reactor Temp (C)
2500
Examination of Heat Profile
Reaction had initiated before heat-up
Autocatalytic profile
No Basis of Safety
NCS + THF: Adiabatic Testing
130
125
120
115
110
105
100
95
90
85
80
75
70
65
60
55
50
45
40
35
30
25
20
15
10
3.5
3.3
3.1
Temp
Pressure
2.7
2.5
2.3
Immediate interaction upon reaching ambient temp
→ Search for new solvent system by synthetic chemist
& safety scientist
Safety & quality concern
2.1
1.9
1.7
0
50
100
150
200
Time (min)
250
300
350
1.5
400
Pressure (bar)
Temperature (oC)
2.9
Solvent Screening for Safety & Performance
Chemistry ran better than ever in dioxane-water
–
Reduced impurities
Worked to establish basis of safety
NCS Interaction with 50-50 Dioxane-Water
With SM present, reaction
kinetics are favored over
NCS-solvent interaction
(and gives off much less
heat)
atr = 15 & 35 ⁰C
No permanent gas evolution
Mass spectroscopy data on NCS/dioxane interaction shows ring-opening and
chlorination of the dioxane moiety
Reaction Calorimetry on Desired & Secondary
Reactions
Comparative RC1 data showing NCS
interaction with 50-50 dioxane water

•
Data plotted from two RC1 experiments, both
with 1.4 eq NCS, 10 vol dioxane/water, 80 °C
•
NCS – dioxane – water
•
NCS – dioxane – water – SM
Kinetic basis of safety established due to system preference for desired reaction to
undesired solvent interaction.
•
Recommendation to plant – ensure all materials (NCS and starting material)
have been charged prior to heat-up to avoid undesired interaction
Another example of N-Halosuccimide Interaction
First Scaleup Campaign:
NBS showed an initial incompatibility with the solvent of choice
– Switched to chlorinated solvent
Aprotic solvent necessary for second transformation
A cumbersome solvent swap was performed between the two
transformations
Scale-up required adjustments and simplifications to two-solvent
system
NBS + DMA
100
90
Temperature deg C
80
Chemistry preference for
dimethylacetamide
as aprotic solvent
Experiment 1
70
Experiment 2
60
50
40
Onset
PATRa
40 °C
35 °C
23 °C
25 °C
30
20
0
100
200
300
400
500
600
700
800
Time (min)
No significant improvement in the safety profile using recrystallized NBS
The maximum rate of self-heating was moderate.
No significant pressurization was observed;
– Decomposition did not produced permanent gaseous by-products.
Reaction Chemistry
120
1800
Rxn 1: NBS solid Addition
1600
Heat
Rate of Heat Output (W/kg)
1400
Conv
80
1200
Addn
1000
60
800
40
600
400
20
200
NBS Addition (%) or Thermal Conversion (%)
100
Rxn 2: Substrate Soln Addition
0
120
Heat
180
-200
Addn
-20
0
5
10
15
20
25
30
35
40
45
100
160
50
Time (min)
Conv
80
Rate of Heat Output (W/kg)
140
120
60
100
40
80
60
20
40
0
20
0
-20
0
patr 20 ºC for both transformations
5
10
15
20
25
30
Time (min)
35
40
45
50
55
Reagent Addition (%) or Thermal Conversion (%)
200
0
Sub-Ambient Calorimetry at Two Concentrations
NBS-DMA Experiment
7.3 wt % NBS in
DMA
13.0 wt % NBS in
DMA
Observed Onset Temp
32. 47 ºC
34.03 ºC
Self-Heat Rate at To
0.023 ºC/min
0.031 ºC/min
Temp at Max. Rate
52.03 ºC
74.10 ºC
Maximum Self-Heat Rate
0.343 ºC/min
2.43 ºC/min
Final Adiabatic Temp
67.20 ºC
121.20 ºC
Adiabatic Temp Rise
34.80 ºC
80.30 ºC
Adiabatic Temp Rise (Φ corrected) 60.55 ºC
130.09 ºC
Final Adiabatic Temp
93.02 ºC
164.12 ºC
Enthalpy of Reaction
400 kJ/mol
400 kJ/mol
Time to Maximum Rate @ 20 ºC
10 hours
5 hours
Time to Maximum Rate @ 0 ºC
300 hours; 12.5 days
66.7 hours; 2.77 days
The onset of exothermic activity not concentration dependent
Adiabatic temperature rise, maximum self-heating rate, moderate,
concentration dependent
Worse-case analysis of the unintended reaction of NBS and
dimethylacetamide must be dependent on process concentration
RC1 Experiments on NBS/DMA Stability
NBS into DMA @ 20 °C:
Color change
– Clear to orange between 2-3 h
Heat spike; 250 kJ/kg; patr =10 °C; maximum 67 W/kg.
– Orange solution no longer reactive with starting material
NBS in DMA at ambient temperature has limited stability of a few hours.
NBS into DMA a @ 0 °C and held for 24 hours.
A color change to bright orange by the end of the experiment
– Thermal activity was below the level of instrument noise
– Use test unsuccessful
Solution NBS in DMA at 0 ºC also has limited stability of less than 24 hours.
Basis of Safety
NBS in dimethylacetamide = unstable, self-heating mixture, but
This combination safe in the proposed process
– NBS will react preferentially with starting material over the solvent DMA.
Worse-case scenario of total decomposition of NBS in DMA:
– Heat generation will not bring the reaction mixture into a critical, runaway
situation
Loss of cooling = loss of batch
Caveats:
Changes in reaction concentration and/or processing temperature must be reevaluated with respect to the stability of the NBS + DMA interaction
NBS must not be premixed with dimethylacetamide.
– Any proposed process change involving a solution charge of NBS must
be thoroughly evaluated for safety implications.
Another Incompatibility Example
A request for process safety examination on an older process
Feedstock of pyrophosphoryl chloride in THF
– Concentrated feedstock
– No competing reactions to minimize interaction
More potentially hazardous than previous process
– Possibility of many maloperations to initiate interaction
– Feedstock prepared too soon, forgotten, remainder sent to
inappropriate waste, etc.
Warm climate at processing facility
Cl
Cl
O
O
P
P
O
Cl
Cl
Initial ARC Experiment on Feedstock
110
Exp
terminated
100
90
Temperature (oC)
80
70
60
50
40
30
20
0
25
50
75
100
125
150
Time (min)
Initial exotherm on mixing proceeds to runaway
Onset at ambient temperatures 20-30 ºC
175
200
Cryogenic ARC Experiment
Cryogenic ARC Experiment
Approximately 13 °C, an exotherm is detected
At ~65 °C, the rate of self-heating increased
Once the sample reaches 170 °C an exothermic runaway occurs with
a huge pressure increase
Significant permanent pressure is generated due to by-product, noncondensable gas(es) of unknown identity
A very large adiabatic temperature rise (> 450 °C) is achievable
Onset Temperature
Rate at 12.77 °C = 0.21 °C/min
The temperature rate at 13 °C is very close to the sensitivity threshold
Some self-heating can be detected as low as 1 °C
Time to Maximum Rate
At 30 °C, the maximum reaction rate will be reached in approximately
460 min or 7.7 h. (TMR @ 13 °C = 16.9 h)
< 8 h to detect the mal-operation, take corrective action, and mitigate
the mal-operation before a catastrophic situation is reached.
– A safety critical temperature in a real system will be achieved earlier
An excess of pyrophosphoryl chloride is used in this process.
– Post-addition reaction mixture contains a potentially self-heating interaction
of this reagent with THF
– Low operating temperature (-10 °C)
– Higher dilution (5.8 wt%)
– Mal-operations prior to the aqueous
quench can lead to a loss of control
Loss of cooling, overcharge of
reagent solution, prolonged hold
Protective Basis of Safety
Feedstock not admixed until actual reaction vessel charged and at
operating temperature
Feed tank vented with temperature monitoring
Emergency Quench tank prepared
Defined temperature of emergency response
Immediate post-reaction feed tank rinse to quench tank
Investigation of a Laboratory Runaway
Hazards of a Hydrogen Peroxide Epoxidation
Runaway Laboratory Oxidation
5 g Epoxidation run
– No incident
– Mediocre yield and quality
30 g Epoxidation setup to run overnight at ambient temp
– Chemist returns in morning to find mess
Another 30 g experiment setup
– Short induction period
– Violent ejection from flask
– Flask hot to touch; gas evolution uncertain
Reaction Chemistry
Literature Reference:
OH + H2O2
H2WO4
NaOAc
O
OH
MeOH
2, 4-pentadien-1-ol
Actual Reaction:
OH + H2O2
t rans, t rans-2, 4-hexadien-1-ol
H2WO4
NaOAc
O
OH
MeOH
target epoxide
OMe
MeO
OH
ring-opened by-product
Reaction Conditions
OH + H2O2
t rans, t rans-2, 4-hexadien-1-ol
H2WO4, NaOAc
MeOH
Batch reaction
Allylic alcohol added last in one portion
– 1.5 eq 30% Hydrogen peroxide
– 4 Vol methanol
– 0.1 eq Tungstic acid
– 0.3 eq Sodium acetate
Catalyst loading 10X literature
Target epoxide
– Only one literature reference
– No preparative procedure
O
OH
target epoxide
Preliminary Analysis: Theoretical Calculations
Olefin + H2O2 → Epoxide + water
– CHETAH & Examples of ∆Hf from the literature
ΔHrxn = -235 kJ/mol; ΔTad = 154 ºC
Heat sufficient to bring reaction to reflux; vaporize 56% of total methanol
Transformation of target epoxide to ring-open by-product; Low enthalpy
process: ≈ -20 kJ/mol
Theoretical Models of the Enthalpy of Epoxidation
Olefin
OH + H2O2
OH
O
OH
+ H2O
ΔHf
(kJ/mol)
-172
4.3
Epoxide
O
OH
O
53
O
ΔHf
(kJ/mol)
ΔHrxn
(kJ/mol)
-298
-224
-131
-233
-98
-249
Reaction Calorimetry
110
650
H2 O2 Addn
Thermal Conv.
Total Heat Output:
– -257 kJ/mol
Adiabatic temp rise:
– 155 ºC
Maximum rate:
– 588 W/kg
Rate of Heat Output (W/kg)
550
90
80
450
70
Heat
60
350
50
250
40
30
150
20
10
50
0
-50
0
1
2
3
4
5
Reaction Time (h)
No gas evolution
5% heat during addition
Final product:
– 9% starting material & 91% ring-opened by-product
Autocatalytic profile
Vessel with good heat transfer runaway is avoided
6
7
8
-10
H2O2 Addition or Thermal Conversion (%)
100
Heat Profile: 2 Hour Addition Time
Longer addition time:
Still poor control
Thermal Stability Studies: ArSST
ARSST Experiments on Reaction Mixtures
Entry
Experimental Conditions
Self-Heat Rate (°C/min)
Self-Pressurization Rate
(psi/min)
Maximum
Rate
Initiation
Temperature
Maximum
rate
Initiation
Temperature
Pressure
Gain
(psi)
1
0.01 eq H2WO4; no 1
82
47 ºC
2.4
42 ºC
1.7
2
0.1 eq H2WO4; no 1
71
40 ºC
11.5
33 °C
11.6
3
0.1 eq Na2WO4; no 1
8300
45 ºC
618
40 ºC
13.7
4
0.01 eq H2WO4; with 1
4970
40 ºC
70
35 ºC
0.3
5
0.1 eq H2WO4; with 1
6760
42 ºC
480
35 ºC
0.3
6
No H2WO4 catalyst; with 1
314
65 ºC
309
55 ºC
4.9
7
No H2WO4 catalyst; no 1
15
105 °C
7.9
95 °C
12
8
0.1 eq H2WO4; no 1; no
methanol
3730
45 °C
7510
35 °C
30
Blank Experiment 1: 0.1 eq H2WO4
Self-Heat & Pressurization Rates
o
C/min
10
psi/min
Pressure vs Temperature
1
315
310
0.1
20
25
30
35
40
45
50
55
60
65
70
75
Temperature (oC)
80
85
90
95 100 105 110 115
Pressure (psig)
Self-Heat Rate (oC/min) & Self-Pressurization Rate
(psi/min)
100
305
306 psig
300
295
294.4 psig
290
20
30
40
50
60
70
80
Temperature (oC)
90
100
110
120
Blank Reactions:
Hydrogen Peroxide decomposition at low temperatures
– Surprisingly low onset (33-47 ºC) for common synthetic
methodology
– Pressure more sensitive than heat
– Tungsten/H2O2: Not specifically reported in literature
Gaseous decomposition
– Permanent non-condensable gas
– ~1/3 of hydrogen peroxide loading
Severity of runaway function of catalyst loading
Sodium tungstate far more severe than tungstic acid/sodium acetate
– Buffered pH = stabilizing effect
Self-Heat Rate (oC/min) & Self-Pressurization Rate
(psi/min)
100
o
C/min
10
psi/min
1
0.1
20
25
30
35
40
45
50
55
60
65
70
75
Temperature (oC)
80
85
90
95 100 105 110 115
Decomposition in the Presence of Hexadien-1-ol
Self-Heat & Pressurization Rates – 0.01 eq W
10000
100
o
1000
10
100
10
1
1
0.1
0.1
Self-Heat & Pressurization Rates – 0.1 eq W
100000
1000
psi/min
0.01
20
40
60
80
100
120
140
160
10000
180
o
C/min
Temperature (oC)
100
1000
10
100
1
10
0.1
1
0.01
0.1
0.01
0.001
20
30
40
50
60
70
80
90
100 110 120 130 140 150 160 170 180
Temperature (oC)
Self-Pressurization Rate (psi/min)
0.01
Self-Heating Rate (oC/min)
Self-heat Rate (oC/min)
psi/min
Self-Pressurization Rate (psi/min)
C/min
Hexadien-1-ol reactions
Extreme self-heating scenarios
Little or no non-condensable gas formation
Hydrogen peroxide not available for decomposition
Target epoxide thermally unstable at low onset temperatures (~40 ºC)
100000
10000
10000
Self-Heat Rate (oC/min)
1000
100
100
10
10
Heat & Pressure:
Blank
1
1
0.1
0.1
0.01
0.01
20
30
40
50
60
70
80
Reaction Temperature (oC)
90
100
110
Self-Pressurization Rate (psi/min)
1000
Heat & Pressure:
with Sorbitol
Root Causes
Moderately exothermic batch reaction with high patr, high catalyst
loading, and autocatalytic nature
Tungsten catalyzed decomposition of hydrogen peroxide at fairly low
temperatures
– Possible non-condensable gas formation
Thermal and chemical instability of target molecule
Poor cooling capacity of vessel configuration in lab; TNR exceeded
= Classic runaway scenario!
Competing secondary decomposition processes
Metal catalyzed decomposition of H2O2
Decomposition of target epoxide
Recommendations for Laboratory Risk
Assessments
Chemistry unsuitable for scale-up
– Target epoxide probably not a suitable synthetic intermediate
No procedural changes necessary
Incident caused by combination of factors which due diligence and desk
screening by laboratory chemist would not detect.
– Some complacency in following literature procedure for closely related
molecule
Ordinary laboratory safety procedures mitigated consequence to cleanup job
Existing procedures adequately addressed consequences of unknown
chemical interaction.
However,
Although tungsten catalyst + H2O2 is a green reagent, the development
chemist must be aware of potential hazards and barriers to scale-up
Heterogeneous Batch Reactions in
DMSO at Elevated Temperatures
Or
‘Almost Fooled’
Reaction & Proposed Mechanism
X
+ ArOH
Br
X
Cs2CO3, Cu2O
Ar
N,N-dimethylglycine
DMSO 3 vol.
> 120 oC
+ CsHCO3
+ CsBr
O
+ CuO
+
OH
N
O
Heterogeneous batch reaction heated to 120 oC for 5-10 hrs
Cu(I)
O
Br
Ar
R
Cu(III)
Br
Reductive
elimination
-Cu(I)
Oxidative addition (2e- are
added to Br-Ar bond to make
electrophilic species)
Ar
O-Cs+
Cu(III)
O
R
O
Ar
+CsBr + HCsCO3
O
N
Cu(I)
N,N-Dimethylglycine is added to make Cu more nucleophilic
DMSO is Not an Inert Solvent
DMSO reacts violently or explosively with:
–
Acetyl chloride, benzenesulfonyl chloride, cyanuric chloride, phosphorus
trichloride, phosphoryl chloride, tetrachlorosilane, sulfur dichloride, disulfur
dichloride, sulfuryl chloride or thionyl chloride.
Violent reactions are explained in terms of exothermic polymerisation of
formaldehyde produced under a variety of conditions by interaction of the
sulfoxide with reactive halides, strong acidic or basic reagents
It is believed that HBr catalyses DMSO decomposition at elevated
temperatures, which is then accelerated by its decomposition product,
dimethylsulfide, resulting in rapid temperature and pressure rises.
The autocatalytic nature of the DMSO decomposition in presence of cesium
bromide is also described
Thermal Stability of DMSO by ARC
280
60.0
DMSO
260
240
50.0
220
Temperature (°C)
180
160
140
40.0
30.0
120
100
20.0
80
60
Temperature
40
20
Pressure
Recommended maximum processing temp ~130 °C
Various 'additives' can dramatically reduce this figure
0
0
200
400
600
Time (min.)
800
1000
10.0
0.0
1200
Pressure (bara)
oC
Exothermic decomposition from 162
Exotherm detected from 162°C
Significant gas generation
Runaway near the boiling point
200
Thermal stability by DSC
No significant issues in the thermal stability of individual components
Real issue in stability of DMSO at elevated temperatures in the
reaction matrix
Isoage @ 120 oC (Tj) for 24 hrs, then HWS
160oC
135oC
Exotherm detected from 120 oC, came out of exotherm after ~13.5 hrs
∴ Lower the process temperature to 100 °C
RC1: Batch Process @ 100 oC
105
120
95
Temperature
100
80
75
65
60
55
40
45
20
Heat Flow
35
25
0
0
20
40
60
80
100
120
140
160
180
200
Time (mins)
• Heat-up over 30 min: ∆Ta d= 12 oC, ∆H = 120 kJ/kg
• Remaining rxn: ∆ Tad = 18 oC, ∆H = 180 kJ/kg
• No gas generated
• Reaction was complete by HPLC after 6 hrs @ 100 oC
Temperature [kg]
Heat Flow [W/kg]
85
DMSO + Additives
DMSO + Cs2CO3 HWS
No safety problems
observed near reaction
temperature of 100 oC
→ Reaction appeared
fully characterized for
safety
DMSO + Cs2CO3 +
Cu2O +
dimethylglycine
Last Set of Experiments: VSP – Stirred System
600
1600
1400
1200
400
1000
300
800
600
200
400
100
0
Pressure (psia)
Temperature (oC)
500
200
0
200
400
Time (mins)
600
800
0
Batch @ 110 °C overnight:
Slow exotherm
After ~10 h; rapid exotherm, rapid pressure;
– > 1000 psi/min
– Bursting of test container
– Probably autocatalytic
Onset problematic, dependent on reaction conditions
Cooling failure on scale could lead to violent loss of containment
In a system with agitation, previously undetected exotherm is revealed
Assumed to be due to better contact between DMSO & CsBr
VSP2, Cut-off @ 110 oC, Runaway after~ 10 hours
600
1600
1400
1200
400
1000
300
800
600
200
400
100
0
200
0
200
400
Time (mins)
600
800
Pressure (psia)
Temperature (oC)
500
0
• No Basis of Safety
• Move away from DMSO & select alternative aprotic
solvent
• Chemist quickly reworks process
Modified chemistry (NMP) VSP2, cut-off @ 130oC
X
+ ArOH
N,N-dimethylglycine
NMP 3 vol.
> 120 oC
Ar
+ CsHCO3
+ CsBr
O
+ CuO
160
140
140
manual cool-dow n
initiated
120
Temperature ( o C)
120
100
100
80
80
60
60
40
40
20
20
0
0
200
400
600
800
Time (min)
1000
1200
1400
+
OH
N
O
0
1600
Pressure (psia)
Br
X
Cs2CO3, Cu2O
Conclusions
DSC & ARC data may not be sufficient for assessment of
heterogeneous batch reactions
– Combination of techniques to establish basis of safety
Heterogeneous batch reaction to be investigated under adiabatic
conditions with agitation
Discourage the use of DMSO at elevated temperatures in presence of
reactive halides
Early Process Safety Incident:
1386: Geoffrey Chaucer, Canterbury Tales: THE CANON’S YEOMAN’S TALE
It happens, like as not,
There’s an explosion and good-bye to the pot!
These metals are so violent when they split
Our very walls can scarce standup to it……
Some said the way the fire was made was wrong;
Others said, “No - the bellows. Blown too strong.”……
I’ve no idea why the thing went wrong;
Recriminations through the air were hot and strong.
“Well,” said my lord, “there’s nothing more to do.
I’ll note these dangers for another brew;”
Thanks to the WW Process Safety Team at GSK