CSIRO Publishing blank image blank image blank image blank imageBooksblank image blank image blank image blank imageJournalsblank image blank image blank image blank imageAbout Usblank image blank image blank image blank imageShopping Cartblank image blank image blank image You are here: Journals > Australian Journal of Chemistry   
Australian Journal of Chemistry
Journal Banner
  An international journal for chemical science
blank image Search
blank image blank image
blank image
  Advanced Search

Journal Home
About the Journal
Editorial Structure
For Advertisers
Online Early
Current Issue
Just Accepted
All Issues
Virtual Issues
Special Issues
Research Fronts
Sample Issue
For Authors
General Information
Submit Article
Author Instructions
Open Access
For Referees
Referee Guidelines
Review an Article
For Subscribers
Subscription Prices
Customer Service
Print Publication Dates
Library Recommendation

blue arrow e-Alerts
blank image
Subscribe to our Email Alert or RSS feeds for the latest journal papers.

red arrow Connect with us
blank image
facebook twitter logo LinkedIn

Affiliated with RACI

Royal Australian Chemical Institute
Royal Australian
Chemical Institute


Article << Previous     |     Next >>   Contents Vol 66(2)

Characterization of Dispersion Effects on Reaction Optimization and Scale-Up for a Packed Bed Flow Hydrogenation Reactor

John W. Eschelbach A D, David Wernick B, Marian C. Bryan C and Elizabeth M. Doherty C

A Amgen, Inc. – Research Automation and Technology, Thousand Oaks, California, CA 91320, USA.
B Department of Chemical and Biomolecular Engineering, University of California at Los Angeles, Los Angeles, California, CA 90095, USA.
C Amgen, Inc. – Medicinal Chemistry Research Technologies, Therapeutic Discovery, Thousand Oaks, California, CA 91320, USA.
D Corresponding author. Email: jeschelb@amgen.com

Australian Journal of Chemistry 66(2) 165-171 http://dx.doi.org/10.1071/CH12450
Submitted: 5 October 2012  Accepted: 31 October 2012   Published: 17 December 2012

PDF (524 KB) $25
 Supplementary Material
 Export Citation

A well known advantage of flow chemistry reactors in chemical synthesis is the ability to screen multiple catalysts and reaction parameters with optimal conditions scaled accordingly. This approach, however, consumes significant quantities of material as the reactor must be equilibrated with the reactants in a continuous, steady-state mode before the start of the reaction. In this work we explore a screening and reaction approach using bolus injections, which is more conducive to the lower material consumption that may be required in a drug discovery setting. A commercially available ThalesNano H-Cube® was evaluated to determine the practicality of this approach for heterogeneous hydrogenations. When working with boluses in flow systems, one of the biggest limitations can be the inherent dispersion of the reactant stream caused by the reactor. The dispersion on the H-Cube® was characterized to determine the minimum volume for the reactor to reach a steady-state. The H-Cube® fluidics and heating coil were found to generate significantly more dispersion than the reaction cartridge (CatCart®) itself, increasing the minimum volume of injection required to achieve steady-state. A 2 mL injection was found as a good compromise between maximizing material conservation and sufficient volume of reaction at steady-state condition. Conditions optimized at 2 mL screening scale were successfully scaled five-fold, while lower volume bolus injections were shown to be less predictable. A stacked injection protocol using lower volume boluses was found to be a reliable alternative to scale reactions while efficiently conserving material. This application of small bolus injections to flow reaction screening and scale-up provides a desirable alternative to traditional continuous flow approaches in the material-limited discovery setting.


[1]  (a) J. Kobayashi, Y. Mori, K. Okamoto, R. Akiyama, M. Ueno, T. Kitamori, S. Kobayashi, Science 2004, 304, 1305.
         | CrossRef | CAS |
      (b) B. Desai, C. O. Kappe, J. Comb. Chem. 2005, 7, 641.
         | CrossRef |
      (c) R. V. Jones, L. Godorhazy, N. Varga, D. Szalay, L. Urge, F. Darvas, J. Comb. Chem. 2006, 8, 110.
         | CrossRef |
      (d) M. Irfan, T. N. Glasnov, C. O. Kappe, ChemSusChem 2011, 4, 300.
         | CrossRef |
      (e) M. A. Mercadante, C. B. Kelly, C. Lee, N. E. Leadbeater, Org. Process Res. Dev. 2012, 16, 1064.
         | CrossRef |
      (f) S. Newton, S. V. Ley, E. C. Arcé, D. M. Grainger, Adv. Synth. Catal. 2012, 354, 1805.
         | CrossRef |
      (g) S. V. Ley, I. R. Baxendale, CHIMIA 2008, 62, 162.
         | CrossRef |

[2]  (a) R. C. Wheeler, E. Baxter, I. B. Campbell, S. J. F. Macdonald, Org. Process Res. Dev. 2011, 15, 565.
         | CrossRef | CAS |
      (b) R. Jones, L. Godorhazy, D. Szalay, J. Gerencser, G. Dorman, L. Urge, F. Darvas, QSAR Comb. Sci. 2005, 24, 722.
         | CrossRef |
      (c) B. Clapham, N. S. Wilson, M. J. Michmerhuizen, D. P. Blanchard, D. M. Dingle, T. A. Nemcek, J. Y. Pan, D. R. Sauer, J. Comb. Chem. 2008, 10, 88.
         | CrossRef |

[3]  (a) G. N. Doku, W. Verboom, D. N. Reinhoudt, A. van den Berg, Tetrahedron 2005, 61, 2733.
         | CrossRef | CAS |
      (b) J. P. McMullen, K. F. Jensen, Annu. Rev. Anal. Chem. 2010, 3, 19.
         | CrossRef |

[4]  (a) M. Baumann, I. R. Baxendale, S. V. Ley, N. Nikbin, C. D. Smith, J. P. Tierney, Org. Biomol. Chem. 2008, 6, 1577.
         | CrossRef | CAS |
      (b) I. R. Baxendale, S. V. Ley, C. D. Smith, L. Tamborini, A.-F. Voica, J. Comb. Chem. 2008, 10, 851.
         | CrossRef |
      (c) I. R. Baxendale, S. C. Schou, J. r. Sedelmeier, S. V. Ley, Chem. – Eur. J. 2010, 16, 89.
         | CrossRef |

[5]  (a) K. D. Nagy, B. Shen, T. F. Jamison, K. F. Jensen, Org. Process Res. Dev. 2012, 16, 976.
         | CrossRef | CAS |
      (b) F. E. Valera, M. Quaranta, A. Moran, J. Blacker, A. Armstrong, J. T. Cabral, D. G. Blackmond, Angew. Chem. Int. Ed. 2010, 49, 2478.
         | CrossRef |

[6]  (a) R. C. Wheeler, O. Benali, M. Deal, E. Farrant, S. J. F. MacDonald, B. H. Warrington, Org. Process Res. Dev. 2007, 11, 704.
         | CrossRef | CAS |
      (b) A. R. Bogdan, N. W. Sach, Adv. Synth. Catal. 2009, 351, 849.
         | CrossRef |
      (c) P. P. Lange, A. R. Bogdan, K. James, Adv. Synth. Catal. 2012, 354, 2373.
         | CrossRef |

[7]  J. J. W. Bakker, M. M. P. Zieverink, R. W. E. G. Reintjens, F. Kapteijn, J. A. Moulijn, M. T. Kreutzer, ChemCatChem 2011, 3, 1155.
         | CrossRef | CAS |

[8]  M. C. Bryan, D. Wernick, C. D. Hein, J. V. Petersen, J. W. Eschelbach, E. M. Doherty, Beilstein J. Org. Chem. 2011, 7, 1141.
         | CrossRef | CAS |

[9]  (a) C. T. Martha, N. Elders, J. G. Krabbe, J. Kool, W. M. A. Niessen, R. V. A. Orru, H. Irth, Anal. Chem. 2008, 80, 7121.
         | CrossRef | CAS |
      (b) C. J. Welch, X. Gong, J. Cuff, S. Dolman, J. Nyrop, F. Lin, H. Rogers, Org. Process Res. Dev. 2009, 13, 1022.
         | CrossRef |

[10]  H. S. Fogler, Elements of Chemical Reaction Engineering 2005, 4th edn (Prentice Hall: New Jersey, NY).

[11]  K. R. Knudsen, J. Holden, S. V. Ley, M. Ladlow, Adv. Synth. Catal. 2007, 349, 535.
         | CrossRef | CAS |

Subscriber Login


Legal & Privacy | Contact Us | Help


© CSIRO 1996-2016