The Evolution of Pd
Conspectus: Aromatic fluorides are prevalent in both agrochemical and pharmaceutical agents. However, methods for their rapid and general preparation from widely available starting materials are limited. Traditional approaches such as the Balz-Schiemann and Halex reactions require harsh conditions t...
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| Format: | Article |
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American Chemical Society (ACS)
2018
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| Online Access: | http://hdl.handle.net/1721.1/113040 https://orcid.org/0000-0003-3928-2984 https://orcid.org/0000-0003-3875-4775 |
| _version_ | 1826213920510050304 |
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| author | Sather, Aaron C. Buchwald, Stephen Leffler |
| author2 | Massachusetts Institute of Technology. Department of Chemistry |
| author_facet | Massachusetts Institute of Technology. Department of Chemistry Sather, Aaron C. Buchwald, Stephen Leffler |
| author_sort | Sather, Aaron C. |
| collection | MIT |
| description | Conspectus: Aromatic fluorides are prevalent in both agrochemical and pharmaceutical agents. However, methods for their rapid and general preparation from widely available starting materials are limited. Traditional approaches such as the Balz-Schiemann and Halex reactions require harsh conditions that limit functional group tolerance and substrate scope. The use of transition metals to affect C-F bond formation has provided some useful alternatives, but a broadly applicable method remains elusive. In contrast to the widespread use of Pd[superscript 0] /Pd [superscript II] catalysis for aryl-Z bond formation (Z = C, N, O), the analogous C-F cross-coupling process was unknown until fairly recently. In large part, this is due to the challenging Ar-F reductive elimination from Pd(II) intermediates. We have discovered that certain biaryl monophosphine ligands are uniquely capable of promoting this transformation. In this Account, we describe the discovery and development of a Pd-catalyzed C-F cross-coupling process and the systematic developments that made this once hypothetical reaction possible.Key to these developments was the discovery of an unusual in situ ligand modification process in which a molecule of substrate is incorporated into the ligand scaffold and the identity of the modifying group is crucial to the outcome of the reaction. This prompted the synthesis of a variety of "premodified" ligands and the identification of one that led to an expanded substrate scope, including (hetero)aryl triflates and bromides. Contemporaneously, a new Pd(0) precatalyst was also discovered that avoids the need to reduce Pd(II) in situ, a process that was often inefficient and led to the formation of byproducts.The use of inexpensive but hygroscopic sources of fluoride necessitates a reaction setup inside of a N[subscript 2] -filled glovebox, limiting the practicality of the method. Thus, a preformed wax capsule was designed to isolate the catalyst and reagents from the atmosphere and permit benchtop storage and setup. This new technology thus removes the requirement to employ a glovebox for the aromatic fluorination process and other air-sensitive protocols.In every catalyst system that we have studied to date, we observed the formation of regioisomeric fluoride side products. Through deuterium labeling studies it was found that they likely arise from a deprotonation event resulting in the formation of HF and a Pd-benzyne intermediate. Through an investigation of the mechanism of this undesired pathway, a new ligand was designed that substantially reduces the formation of the aryl fluoride regioisomer and even allows room-temperature Ar-F reductive elimination from a Pd(II) intermediate. |
| first_indexed | 2024-09-23T15:56:39Z |
| format | Article |
| id | mit-1721.1/113040 |
| institution | Massachusetts Institute of Technology |
| last_indexed | 2024-09-23T15:56:39Z |
| publishDate | 2018 |
| publisher | American Chemical Society (ACS) |
| record_format | dspace |
| spelling | mit-1721.1/1130402022-10-02T05:16:29Z The Evolution of Pd Sather, Aaron C. Buchwald, Stephen Leffler Massachusetts Institute of Technology. Department of Chemistry Sather, Aaron C. Buchwald, Stephen Leffler Conspectus: Aromatic fluorides are prevalent in both agrochemical and pharmaceutical agents. However, methods for their rapid and general preparation from widely available starting materials are limited. Traditional approaches such as the Balz-Schiemann and Halex reactions require harsh conditions that limit functional group tolerance and substrate scope. The use of transition metals to affect C-F bond formation has provided some useful alternatives, but a broadly applicable method remains elusive. In contrast to the widespread use of Pd[superscript 0] /Pd [superscript II] catalysis for aryl-Z bond formation (Z = C, N, O), the analogous C-F cross-coupling process was unknown until fairly recently. In large part, this is due to the challenging Ar-F reductive elimination from Pd(II) intermediates. We have discovered that certain biaryl monophosphine ligands are uniquely capable of promoting this transformation. In this Account, we describe the discovery and development of a Pd-catalyzed C-F cross-coupling process and the systematic developments that made this once hypothetical reaction possible.Key to these developments was the discovery of an unusual in situ ligand modification process in which a molecule of substrate is incorporated into the ligand scaffold and the identity of the modifying group is crucial to the outcome of the reaction. This prompted the synthesis of a variety of "premodified" ligands and the identification of one that led to an expanded substrate scope, including (hetero)aryl triflates and bromides. Contemporaneously, a new Pd(0) precatalyst was also discovered that avoids the need to reduce Pd(II) in situ, a process that was often inefficient and led to the formation of byproducts.The use of inexpensive but hygroscopic sources of fluoride necessitates a reaction setup inside of a N[subscript 2] -filled glovebox, limiting the practicality of the method. Thus, a preformed wax capsule was designed to isolate the catalyst and reagents from the atmosphere and permit benchtop storage and setup. This new technology thus removes the requirement to employ a glovebox for the aromatic fluorination process and other air-sensitive protocols.In every catalyst system that we have studied to date, we observed the formation of regioisomeric fluoride side products. Through deuterium labeling studies it was found that they likely arise from a deprotonation event resulting in the formation of HF and a Pd-benzyne intermediate. Through an investigation of the mechanism of this undesired pathway, a new ligand was designed that substantially reduces the formation of the aryl fluoride regioisomer and even allows room-temperature Ar-F reductive elimination from a Pd(II) intermediate. National Institutes of Health (U.S.) (Grant R01GM46059) National Institutes of Health (U.S.) (Grant 1F32GM108092-01A1) 2018-01-10T15:50:46Z 2018-01-10T15:50:46Z 2016-09 2016-05 2018-01-09T18:54:48Z Article http://purl.org/eprint/type/JournalArticle 0001-4842 1520-4898 http://hdl.handle.net/1721.1/113040 Sather, Aaron C. and Buchwald, Stephen L. “The Evolution of Pd0/PdII-Catalyzed Aromatic Fluorination.” Accounts of Chemical Research 49, 10 (September 2016): 2146–2157 © 2016 American Chemical Society https://orcid.org/0000-0003-3928-2984 https://orcid.org/0000-0003-3875-4775 http://dx.doi.org/10.1021/ACS.ACCOUNTS.6B00247 Accounts of Chemical Research Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf American Chemical Society (ACS) ACS |
| spellingShingle | Sather, Aaron C. Buchwald, Stephen Leffler The Evolution of Pd |
| title | The Evolution of Pd |
| title_full | The Evolution of Pd |
| title_fullStr | The Evolution of Pd |
| title_full_unstemmed | The Evolution of Pd |
| title_short | The Evolution of Pd |
| title_sort | evolution of pd |
| url | http://hdl.handle.net/1721.1/113040 https://orcid.org/0000-0003-3928-2984 https://orcid.org/0000-0003-3875-4775 |
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