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Kinetics of SnAr Reaction. Rob Woodward.
1. Kinetics of a SnAr
Reaction
Robert Woodward – DynoChem User Meeting May 2011
2. Structure of talk
• Introduction to the chemistry
• The Iterative Dynochem Cycle
• Fitting the data
• Linear Free energy relationships
• Predictive chemistry
• Conclusions and summary
Simul
Optim.
(test )
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3. The Chemistry
OH
F CN
F CN O
S
O MSP
O
F NMP, xylene
K2CO3 O
3 eq S
130oC SOLID
DFBN O
Monoaryl Sulfone
• First step in a manufacture of a diabetes medication
• High temperature reaction
• Solid / Liquid system – mass transfer may be important
• Large excess of difluoride required
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4. The Problem....
• The sulfone requires high temperatures and long
heating periods to give significant conversion
• Upon extended heating times other impurities are
formed
• Impurities difficult to remove in downstream
processing
- CQA’s (cf Bernd Schmidt presentation)
• Does the use on another nucleophile mitigate against
some of these issues?
• Can other chemistry be developed in time to hit required
timelines?
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5. Experiments
• 2 Substrates
- Sulfone
- Sulfide
Sulfone Sulfide
• 4 Temperatures
• 2 Base stoichiometries
• 2 Substrate concentrations
• 2 Dilutions
• Total of 10 experiments for each substrate
- 4 data points per experiment
- Each data point was a separate run
- Periodic repeats to assess reproducibility
• Experimental runs were carried out with speed of acquisition in mind
- CEM microwave – automated and rapid reactions
- Mettler-Toledo Flexiweigh gave fast and accurate automation
- LCMS for analysis
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6. The Data 90
80
70
% Monoaryl
60
50 Monoaryl
40
30
20
10
0
0 500 1000 1500
Time (sec)
0.9
0.8
0.7
0.6
%Diaryl
0.5
0.4 Diaryl
0.3
0.2
0.1
0
0 500 1000 1500
Time (sec)
100
% Starting material
90
80
70
60
50 S.M.
40
30
20
0 500 1000 1500
Time (sec)
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7. Data
The Dynochem Iterative Cycle
Simulate
Optimise
(test )
The Eyley Wheel
Robert Woodward | May 2011 Dynochem User Meeting
8. Kinetic Scheme
Keq O O
H K
OH O O
+ K2CO3 K
O O
S S
O O
F CN
O O
F CN k1
H K
O O
K + O
O
S F O
O S
O
F CN O CN
O O k2
H K O
O O S
K + O O O
O
S O O
O S S
O O
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9. Kinetic scheme
Keq
Base + Phenol Reagent
k1
Reagent + Substrate Monoaryl + Byproduct
k2
Reagent + Mono Diaryl + Byproduct
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10. Assumptions / Risks
• The mass-transfer rate of the solid K2CO3 is fast compared to the reaction
rate
• This remains the case throughout the reaction
• The heat-up / cool-down period is not taken into account – isothermal
conditions for the specified heating period is assumed.
• The intermediate complex between the phenol and the is reasonable under
the reaction conditions (Khalfina et al, Russ. J. Org. Chem., 2005, 41, 7, 978-
983)
- n.b. no formal deprotonation is required
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11. Fitted data 60
120 C (exp)
50
120 C (calc) F CN
40 125 C (exp)
% Monoaryl
Monoaryl 30 125 C (calc)
130 C (exp) O
20
130 C (calc) O
10 135 C (exp) S
0 135 C (calc) O
0 500 1000 1500
Time (sec)
1.8 120 C (exp)
1.6
1.4
120 C (calc) O CN
1.2 125 C (exp) O
% Diaryl
1 S
Diaryl 0.8
125 C (calc)
O O
0.6 130 C (exp)
0.4 O
130 C (calc)
0.2 S
135 C (exp) O
0
0 500 1000 1500 135 C (calc)
Time (sec)
120 C (exp)
100
90 120 C (calc)
% Starting material
OH
80 125 C (exp)
S.M. 70 125 C (calc)
O
S
60 130 C (exp) O
50 130 C (calc)
40 135 C (exp)
0 500 1000 1500
135 C (calc)
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12. Data fitted as a whole
100
90
80
70
60
Differing amounts
%
50
40 of base
30
20
10
0
0 500 1000 1500
Time (sec)
100
90
80
70
60
%
50
Differing dilutions
40
30
20
10
0
0 500 1000 1500
Time (sec)
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14. That’s all well and good.....
F CN
F CN
O O F
H K F CN
O O -
K
O O
O F
S O
O S
O
SO2Me
• Mechanism explored – second order with a pre-equilibrium
• Exploration of Design Space
- Dynochem tools
• Reaction optimisation against downstream specification possible
- Control of impurities
- Understanding plant time requirements
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15. What about any other nucleophiles? OH
σ (Substituent const.) O
S
0 0.2 0.4 0.6 0.8
Me
-6
-7
-8
Log(k) -9
-10
-11
-12
-13
-14
-15
Parameter Sulfoxide (predicted)
Keq (mol/L) 8 × 104
k1 (L/mol.s) 7.0 × 10-4
Ea1 (kJ/mol) 122
k2 (L/mol.s) 2.4 × 10-5
Ea2 (kJ/mol) 182
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16. Sulfoxide Predictions
120
125 ºC
100
Monoaryl
80
%
60
40
Starting material
20
0
0 5 10 15 20 25
Time (min)
120
115 ºC
100
80
Starting material
%
60
40
Monoaryl
20
0
0 5 10 15 20 25
Time (min)
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17. Conclusions
• Predictive model within the bounds of the experimental plan
• Kinetic data so can predict outside of this
- Reaction space within total knowledge base
• Fit for purpose at C3
- further experimentation required to de-risk any effect from
the solid base used (cf. assumptions)
• Predictivity extended to other nucleophiles for the reaction.
- Risks associated with LFERs
• Delivered specific knowledge base which enabled an
assessment of reactivity between sulfone and sulfide
• Gave greater confidence in manufacturing parameters
• Strategic work shows the validity of this type of approach and
facile, rapid generation of data from microwave kinetic
analysis. (No microwave effect)
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18. What else could we have done?
100
90
80
70
60
%
50
40
30
20
10
0
0 2.5 5 7.5 10 12.5
Time (mins)
Parameter 1 Point Extended Study
Keq (mol/L) 1 × 105 1 × 105
k1 (L/mol.s) 1.4 × 10-5 ± 6 × 10-6 1.2 × 10-5 ± 6 × 10-6
Ea1 (kJ/mol) 122 ± 28 127 ± 20
k2 (L/mol.s) 2.4 × 10-6 ± 1 × 10-6 1.4 × 10-6 ± 8 × 10-7
Ea2 (kJ/mol) 133 ± 29 161 ± 26
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19. Risk versus Effort
0.9
0.8
0.7
0.6
0.5
Risk
0.4
0.3
0.2
0.1
0
0 2 4 6 8 10 12
Effort
• Profile of Effort / Risk will change with development stage
• Later stage development projects will require less risk
- Normally starting from a position from lower risk due to what
is “known” about the chemistry and process
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