Continuous Flow Processes:
New Paradigm in Organic Synthesis
Lecture 3: Interesting Chemistry
1
Flow Process Benefits
Km103
Batch Processes
m 100
Flow Processes
Size (m)
10-3
mm
10-6
um
nm
10-9 Gas Phase
Processes
10-15 10-12 10-9 10-6 10-3 100 103 103
fs ps ns μs ms s min h
Time (s)
“Basics of Flow Microreactor Synthesis”, J. Yoshida, Springer Briefs in Molecular Science, 2015
Flow Process Benefits
[Link]
Flow Syntheses: Reaction Movie
Length/Time
Time is Visible: Time Resolved Synthesis
REACTION MOVIE IN SLOW MOTION
Time is Visible: Can be held CONSTANT
REACTION MOVIE IN PAUSE MODE
4
Micro Reaction Technology in Organic Synthesis, C Wiles and P Watts, 2011, CRC
Time Resolved Synthesis
Kim et al. Science, 2016, 352,6286, 691 5
Time Resolved Synthesis
Continuous Flow of 25 nL: 330 s, 91%
6
Kim et al. Science, 2016, 352,6286, 691
Time Resolved Synthesis
7
Kim et al. Science, 2016, 352,6286, 691
Time Resolved Synthesis
Afesal
(anthelmintic activity)
67%, 5.3g/h
Kim and Yoshida et al. Science, 2016, 352,6286, 691 8
Time Resolved Synthesis
25 nl & 330 s 67%, 5.3g/h
9
Kim et al. Science, 2016, 352,6286, 691
Time Resolved Synthesis
25 nl & 330 s 67%, 5.3g/h
10 ml & 330 s @67% ?? g/h
10
Kim et al. Science, 2016, 352,6286, 691
Time Resolved Synthesis
25 nl & 330 s 67%, 5.3g/h
10 ml & 330 s @67% ?? g/h
25 nl : 10 ml (1:4x105)
11
Kim et al. Science, 2016, 352,6286, 691
Time Resolved Synthesis
25 nl & 330 s 67%, 5.3g/h
10 ml & 330 s @67% ?? g/h
25 nl : 10 ml (1:4x105)
5.3g/h = 2.1 ton/h
12
Kim et al. Science, 2016, 352,6286, 691
Time Resolved Synthesis
25 nl & 330 s 67%, 5.3g/h
10 ml & 330 s @67% ?? g/h
25 nl : 10 ml (1:4x105)
5.3g/h = 2.1 ton/h
Throughput: Vol x time
13
Kim et al. Science, 2016, 352,6286, 691
Time Resolved Synthesis
X E Byproduct
Desired Product
E
14
“Basics of Flow Microreactor Synthesis”, J. Yoshida, Springer Briefs in Molecular Science, 2015
Time Resolved Synthesis
Optimum Resident Time of 3ms
“Basics of Flow Microreactor Synthesis”, J. Yoshida, Springer Briefs in Molecular Science, 2015
15
Time Resolved Synthesis
“Basics of Flow Microreactor Synthesis”, J. Yoshida, Springer Briefs in Molecular Science, 2015
16
Time Resolved Synthesis
“Basics of Flow Microreactor Synthesis”, J. Yoshida, Springer Briefs in Molecular Science, 2015
17
Kinetic vs Thermodynamic Control
18
Angew. Chem. Int. Ed. 2009, 48, 8063 –8065
Fast Library Generation
RSC Adv., 2011, 1, 758–760
19
Fast Library Generation
RSC Adv., 2011, 1, 758–760
20
Fast Library Generation
21
The Chemical Record, Vol. 12, 378–390 (2012)
Functionalized Phenols Via
Aerobic Oxidation of Grignard Reagents
Angew. Chem. Int. Ed. 2014, 53, 3353 –3357
22
Functionalized Phenols Via
Aerobic Oxidation of Grignard Reagents
Angew. Chem. Int. Ed. 2014, 53, 3353 –3357 23
Angew. Chem. Int. Ed. 2014, 53, 3353 –3357
24
Functionalized Phenols Via
Aerobic Oxidation of Grignard Reagents
Angew. Chem. Int. Ed. 2014, 53, 3353 –3357 25
Organic Chemistry: REDEFINED
Functionalized Phenols Via
Aerobic Oxidation of Grignard Reagents
27
Functionalized Phenols Via
Aerobic Oxidation of Grignard Reagents
Angew. Chem. Int. Ed. 2014, 53, 3353 –3357 28
C(sp3)–H Functionalizations
Noel and Coworkers, Science 369, 92–96 (2020)
29
C(sp3)–H Functionalizations
Noel and Coworkers, Science 369, 92–96 (2020)
30
C(sp3)–H Functionalizations
Noel and Coworkers, Science 369, 92–96 (2020)
31
32
33
Peptide Drugs
34
Green Chem., 2022, 24, 975–1020
Peptide Drugs
D = diabetes, obesity; ID = immune diseases; C = cancer; MS = multiple sclerosis;
O = osteoporosis; A = acromegaly; CITP = chronic immune thrombocytopenia;
MM = multiple myeloma; IBS = irritable bowel syndrome with constipation;
SBS = short bowel syndrome; and H = hyperparathyroidism
35
Green Chem., 2022, 24, 975–1020
AUTOMATIDE: Flow Solid Phase Peptide Synthesis
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Prof Pentelute MIT: Chembiochem. 2014 Mar 21; 15(5): 713–720
AUTOMATIDE: Flow Solid Phase Peptide Synthesis
37
Prof Pentelute MIT: Chembiochem. 2014 Mar 21; 15(5): 713–720
AUTOMATIDE: Flow Solid Phase Peptide Synthesis
38
Prof Pentelute MIT: Chembiochem. 2014 Mar 21; 15(5): 713–720
Flow Biocatalysis
Int. J. Mol. Sci. 2021, 22, 990
39
Flow Biocatalysis
Good Review Article:
Application of Immobilized Enzymes in Flow Biocatalysis for Efficient Synthesis
Zhongyao Tang, Yuri Oku and Tomoko Matsuda*
Org. Process Res. Dev. 2024, 28, 5, 1308–1326
Int. J. Mol. Sci. 2021, 22, 990
40
Flow Biocatalysis
Nat. Catal. 2019, 2, 1006–1015
41
Flow Biocatalysis
Telescoping
&
Biocatalysis
42
Sustain. Chem. Eng. 2019, 7, 1038–1051
Flow in Agrochemicals
43
Org. Process Res. Dev. 2021, 25, 4, 713
Flow in Agrochemicals
Substituted Thiazoles
44
Org. Process Res. Dev. 2021, 25, 4, 713
Flow in Agrochemicals
3-Bromoisoxazolines
45
Org. Process Res. Dev. 2021, 25, 4, 713
Flow in F & F
46
Beilstein J. Org. Chem. 2021, 17, 1181
Flow in F & F
47
Beilstein J. Org. Chem. 2021, 17, 1181
Flow in F & F
48
Beilstein J. Org. Chem. 2021, 17, 1181
Flow in F & F
Photo-Oxygenation
49
Beilstein J. Org. Chem. 2021, 17, 1181
Autonomous Synthesis
Nat. Commun., 2018, 9 , 1
50
Autonomous Synthesis
Science, 2019, 363
51
Autonomous Synthesis
A total of 5760 reactions evaluated in 3 days
Perera et al., Science 359, 429–434 (2018) 52
Ultrafast Optimization
Perera et al., Science 359, 429–434 (2018) 53
Rufinamide
54
Nature, 2020, 579 , 379
Automation and AI
55
React. Chem. Eng., 2021,6, 756-786