ACS Publications. Most Trusted. Most Cited. Most Read
THE TOTAL SYNTHESIS OF QUININE1

OR SEARCH CITATIONS

My Activity
Publications

Figure 1Loading Img
Download Hi-Res ImageDownload to MS-PowerPointCite This:J. Am. Chem. Soc. 1944, 66, 5, 849
    Article

    THE TOTAL SYNTHESIS OF QUININE1
    Click to copy article linkArticle link copied!

    ACS Legacy Archive
    Other Access Options

    Journal of the American Chemical Society

    Cite this: J. Am. Chem. Soc. 1944, 66, 5, 849
    Click to copy citationCitation copied!
    https://doi.org/10.1021/ja01233a516
    Published May 1, 1944
    Request reuse permissions

    Note: In lieu of an abstract, this is the article's first page.

    Free first page

    Read this article

    To access this article, please review the available access options below.

    Get instant access

    Purchase Access

    Read this article for 48 hours. Check out below using your ACS ID or as a guest.

    Recommended

    Access through Your Institution

    You may have access to this article through your institution.

    Your institution does not have access to this content. Add or change your institution or let them know you’d like them to include access.

    Cited By

    Click to copy section linkSection link copied!

    This article is cited by 81 publications.

    1. Jeffrey I. Seeman. Revolutions in Chemistry: Assessment of Six 20th Century Candidates (The Instrumental Revolution; Hückel Molecular Orbital Theory; Hückel’s 4n + 2 Rule; the Woodward–Hoffmann Rules; Quantum Chemistry; and Retrosynthetic Analysis). JACS Au 2023, 3 (9) , 2378-2401. https://doi.org/10.1021/jacsau.3c00278
    2. Lei Li, Hua-Fei Yang, Qian-Hui Ding, Kun Wei, Yu-Rong Yang. Total Syntheses of Cinchona Alkaloids via Photoredox-Catalyzed Deoxygenative Arylation. Organic Letters 2023, 25 (24) , 4586-4591. https://doi.org/10.1021/acs.orglett.3c01659
    3. Jeffrey I. Seeman, Mark C. House. “For Its Size, the Most Complex Natural Product Known.” Who Deserves Credit for Determining the Structure of Strychnine?. ACS Central Science 2022, 8 (6) , 672-681. https://doi.org/10.1021/acscentsci.1c01348
    4. Francesco Trenti, Kotaro Yamamoto, Benke Hong, Christian Paetz, Yoko Nakamura, Sarah E. O’Connor. Early and Late Steps of Quinine Biosynthesis. Organic Letters 2021, 23 (5) , 1793-1797. https://doi.org/10.1021/acs.orglett.1c00206
    5. Melissa A. Hardy, Brandon A. Wright, J. Logan Bachman, Timothy B. Boit, Hannah M. S. Haley, Rachel R. Knapp, Robert F. Lusi, Taku Okada, Veronica Tona, Neil K. Garg, Richmond Sarpong. Treating a Global Health Crisis with a Dose of Synthetic Chemistry. ACS Central Science 2020, 6 (7) , 1017-1030. https://doi.org/10.1021/acscentsci.0c00637
    6. Mengchao Tong, Sinan Wang, Jinchen Zhuang, Cong Qin, Hao Li, and Wei Wang . Direct Access of the Chiral Quinolinyl Core of Cinchona Alkaloids via a Brønsted Acid and Chiral Amine Co-catalyzed Chemo- and Enantioselective α-Alkylation of Quinolinylmethanols with Enals. Organic Letters 2018, 20 (4) , 1195-1199. https://doi.org/10.1021/acs.orglett.8b00118
    7. Jeffrey I. Seeman. Woodward–Hoffmann’s Stereochemistry of Electrocyclic Reactions: From Day 1 to the JACS Receipt Date (May 5, 1964 to November 30, 1964). The Journal of Organic Chemistry 2015, 80 (23) , 11632-11671. https://doi.org/10.1021/acs.joc.5b01792
    8. Cátia Teixeira, Nuno Vale, Bianca Pérez, Ana Gomes, José R. B. Gomes, and Paula Gomes . “Recycling” Classical Drugs for Malaria. Chemical Reviews 2014, 114 (22) , 11164-11220. https://doi.org/10.1021/cr500123g
    9. Ahmad Al-Mestarihi, Anthony Romo, Hung-wen Liu, and Brian O. Bachmann . Nitrososynthase-Triggered Oxidative Carbon–Carbon Bond Cleavage in Baumycin Biosynthesis. Journal of the American Chemical Society 2013, 135 (31) , 11457-11460. https://doi.org/10.1021/ja404987r
    10. Karina Ap. F. D. Souza and Paulo A. Porto . History and Epistemology of Science in the Classroom: The Synthesis of Quinine as a Proposal. Journal of Chemical Education 2012, 89 (1) , 58-63. https://doi.org/10.1021/ed1003542
    11. Frank-Gerrit Klärner, Maitland Jones, Jr. and Ronald M. Magid. William von Eggers Doering’s Many Research Achievements during the First 65 Years of his Career in Chemistry. Accounts of Chemical Research 2009, 42 (1) , 169-181. https://doi.org/10.1021/ar800100h
    12. Peter Webber and Michael J. Krische. Concise Stereocontrolled Formal Synthesis of (±)-Quinine and Total Synthesis of (±)-7- Hydroxyquinine via Merged Morita−Baylis−Hillman−Tsuji−Trost Cyclization. The Journal of Organic Chemistry 2008, 73 (23) , 9379-9387. https://doi.org/10.1021/jo802165k
    13. Gilbert Stork,, Deqiang Niu,, A. Fujimoto,, Emil R. Koft,, James M. Balkovec,, James R. Tata, and, Gregory R. Dake. The First Stereoselective Total Synthesis of Quinine. Journal of the American Chemical Society 2001, 123 (14) , 3239-3242. https://doi.org/10.1021/ja004325r
    14. Alex C. Bissember. The Quinine Odyssey: A Barometer of the State of Organic Synthesis Over Centuries. Chemistry – A European Journal 2024, 30 (69) https://doi.org/10.1002/chem.202403021
    15. Blaise Kimbadi Lombe, Tingan Zhou, Lorenzo Caputi, Kerstin Ploss, Sarah E. O'Connor. Biosynthetic Origin of the Methoxy Group in Quinine and Related Alkaloids. Angewandte Chemie International Edition 2024, 10 https://doi.org/10.1002/anie.202418306
    16. Blaise Kimbadi Lombe, Tingan Zhou, Lorenzo Caputi, Kerstin Ploss, Sarah E. O'Connor. Biosynthetic Origin of the Methoxy Group in Quinine and Related Alkaloids. Angewandte Chemie 2024, https://doi.org/10.1002/ange.202418306
    17. Takahiro Terunuma, Genki Kawauchi, Yujiro Hayashi. Organocatalyst Mediated Pot‐Economical Total Synthesis of (−)‐Quinine and its Derivatives. Asian Journal of Organic Chemistry 2023, 12 (12) https://doi.org/10.1002/ajoc.202300256
    18. Jeffrey I. Seeman. My first and my latest publication. Journal of Physical Organic Chemistry 2022, 35 (11) https://doi.org/10.1002/poc.4344
    19. Bharti Singal, Jyoti Chhibber‐Goel. The Imminent Threat of Antimalarial Drug Resistance. 2022, 105-131. https://doi.org/10.1002/9783527830589.ch5
    20. Jeffrey I. Seeman. Fifty Years of a Dispute. A Triptych: Why Woodward?**. The Chemical Record 2022, 22 (9) https://doi.org/10.1002/tcr.202200150
    21. Jeffrey I. Seeman. The Many Chemists Who Could Have Proposed the Woodward‐Hoffmann Rules (Including Roald Hoffmann) But Didn't: The Theoretical and Physical Chemists † **. The Chemical Record 2022, 22 (5) https://doi.org/10.1002/tcr.202200052
    22. Vitória de Souza Fernandes, Rafael da Rosa, Lara A. Zimmermann, Kamilla R. Rogério, Arthur E. Kümmerle, Lilian S. C. Bernardes, Cedric S. Graebin. Antiprotozoal agents: How have they changed over a decade?. Archiv der Pharmazie 2022, 355 (2) https://doi.org/10.1002/ardp.202100338
    23. Hamza Hameed, Elizabeth F. B. King, Katerina Doleckova, Barbara Bartholomew, Jackie Hollinshead, Haddijatou Mbye, Imran Ullah, Karen Walker, Maria Van Veelen, Somaia Saif Abou-Akkada, Robert J. Nash, Paul D. Horrocks, Helen P. Price. Temperate Zone Plant Natural Products—A Novel Resource for Activity against Tropical Parasitic Diseases. Pharmaceuticals 2021, 14 (3) , 227. https://doi.org/10.3390/ph14030227
    24. Shinya Shiomi, Hayato Ishikawa. Total Synthesis of Enantioenriched Quinine. Journal of Synthetic Organic Chemistry, Japan 2021, 79 (2) , 145-154. https://doi.org/10.5059/yukigoseikyokaishi.79.145
    25. Jeffrey I. Seeman. The Relationship of William Henry Perkin, Jr. and Sir Robert Robinson: Teacher and Student, then Student and Teacher. Chemistry – A European Journal 2021, 27 (5) , 1576-1591. https://doi.org/10.1002/chem.202002924
    26. Hari Madhav, Nasimul Hoda. An insight into the recent development of the clinical candidates for the treatment of malaria and their target proteins. European Journal of Medicinal Chemistry 2021, 210 , 112955. https://doi.org/10.1016/j.ejmech.2020.112955
    27. Jiarui Yang, Dingsheng Wang, Yadong Li. Identifying the Types and Characterization of the Active Sites on M−X−C Single‐Atom Catalysts. ChemPhysChem 2020, 21 (23) , 2486-2496. https://doi.org/10.1002/cphc.202000595
    28. Brian Wang, Melecio A. Perea, Richmond Sarpong. Übergangsmetallvermittelte Spaltung von C‐C‐Einfachbindungen. Angewandte Chemie 2020, 132 (43) , 19058-19080. https://doi.org/10.1002/ange.201915657
    29. Brian Wang, Melecio A. Perea, Richmond Sarpong. Transition Metal‐Mediated C−C Single Bond Cleavage: Making the Cut in Total Synthesis. Angewandte Chemie International Edition 2020, 59 (43) , 18898-18919. https://doi.org/10.1002/anie.201915657
    30. Yan Jiang, Luca Deiana, Kaiheng Zhang, Shuangzheng Lin, Armando Córdova. Total Asymmetric Synthesis of Quinine, Quinidine, and Analogues via Catalytic Enantioselective Cascade Transformations. European Journal of Organic Chemistry 2019, 2019 (35) , 6016-6023. https://doi.org/10.1002/ejoc.201901003
    31. Fyaz M.D. Ismail. Nature's Armamentarium against Malaria: Antimalarials and Their Semisynthetic Derivatives. 2019, 333-373. https://doi.org/10.1002/9781119436713.ch13
    32. ELIEZER J. BARREIRO. What is hidden in the biodiversity? The role of natural products and medicinal chemistry in the drug discovery process. Anais da Academia Brasileira de Ciências 2019, 91 (suppl 3) https://doi.org/10.1590/0001-3765201920190306
    33. Wentao Liu, Wenfang Qin, Xiaobei Wang, Fei Xue, Xiao‐Yu Liu, Yong Qin. Bioinspired Synthesis of (+)‐Cinchonidine Using Cascade Reactions. Angewandte Chemie 2018, 130 (38) , 12479-12482. https://doi.org/10.1002/ange.201804848
    34. Wentao Liu, Wenfang Qin, Xiaobei Wang, Fei Xue, Xiao‐Yu Liu, Yong Qin. Bioinspired Synthesis of (+)‐Cinchonidine Using Cascade Reactions. Angewandte Chemie International Edition 2018, 57 (38) , 12299-12302. https://doi.org/10.1002/anie.201804848
    35. Daniel H. O' Donovan, Paul Aillard, Martin Berger, Aurélien de la Torre, Desislava Petkova, Christian Knittl‐Frank, Danny Geerdink, Marcel Kaiser, Nuno Maulide. C‐H‐Aktivierung ermöglicht eine kurze Totalsynthese von Chinin und Analoga mit erhöhter Anti‐Malaria‐Aktivität. Angewandte Chemie 2018, 130 (33) , 10897-10901. https://doi.org/10.1002/ange.201804551
    36. Daniel H. O' Donovan, Paul Aillard, Martin Berger, Aurélien de la Torre, Desislava Petkova, Christian Knittl‐Frank, Danny Geerdink, Marcel Kaiser, Nuno Maulide. C−H Activation Enables a Concise Total Synthesis of Quinine and Analogues with Enhanced Antimalarial Activity. Angewandte Chemie International Edition 2018, 57 (33) , 10737-10741. https://doi.org/10.1002/anie.201804551
    37. Anna Rudo, Klaus‐Peter Zeller, Hans‐Ullrich Siehl, Stefan Berger, Dieter Sicker. Chinin, ein legendäres Alkaloid. Chemie in unserer Zeit 2018, 52 (4) , 238-248. https://doi.org/10.1002/ciuz.201800820
    38. Ewa Haładyj, Mariusz Sikora, Anna Felis-Giemza, Marzena Olesińska. Antimalarials – are they effective and safe in rheumatic diseases?. Rheumatology 2018, 56 (3) , 164-173. https://doi.org/10.5114/reum.2018.76904
    39. Jeffrey I. Seeman. On the Relationship between Classical Structure Determination and Retrosynthetic Analysis/Total Synthesis †. Israel Journal of Chemistry 2018, 58 (1-2) , 28-44. https://doi.org/10.1002/ijch.201700079
    40. Scott E. Denmark. Organic Synthesis: Wherefrom and Whither? (Some Very Personal Reflections). Israel Journal of Chemistry 2018, 58 (1-2) , 61-72. https://doi.org/10.1002/ijch.201700085
    41. David Y.‐K. Chen. A Personal Perspective on Organic Synthesis: Past, Present, and Future. Israel Journal of Chemistry 2018, 58 (1-2) , 85-93. https://doi.org/10.1002/ijch.201700113
    42. K. C. Nicolaou. The Emergence and Evolution of Organic Synthesis and Why It is Important to Sustain It as an Advancing Art and Science for Its Own Sake. Israel Journal of Chemistry 2018, 58 (1-2) , 104-113. https://doi.org/10.1002/ijch.201700121
    43. PABLO D.G. MARTINEZ, SUSANN H. KRAKE, MAITIA L. POGGI, SIMON F. CAMPBELL, PAUL A. WILLIS, LUIZ C. DIAS. 2,3,8-Trisubstituted Quinolines with Antimalarial Activity. Anais da Academia Brasileira de Ciências 2018, 90 (1 suppl 2) , 1215-1231. https://doi.org/10.1590/0001-3765201820170820
    44. Jeffrey I. Seeman. R. B. Woodward 's Letters: Revealing, Elegant and Commanding. Helvetica Chimica Acta 2017, 100 (12) https://doi.org/10.1002/hlca.201700183
    45. Donelly A. van Schalkwyk. History of Antimalarial Agents. 2015, 1-5. https://doi.org/10.1002/9780470015902.a0003624.pub3
    46. Bernd Schäfer. Artemisinin. Chemie in unserer Zeit 2014, 48 (2) , 134-145. https://doi.org/10.1002/ciuz.201400645
    47. Ion Neda, Elena Fodor, Catalin V. Maftei, Monica Mihorianu, Horst‐Dieter Ambrosi, M. Heiko Franz. New Members of the Cinchona Alkaloid Family: 9‐Aminoquincorine‐10‐aldehyde and 9‐Aminoquincoridine‐10‐aldehyde. European Journal of Organic Chemistry 2013, 2013 (35) , 7876-7880. https://doi.org/10.1002/ejoc.201301286
    48. Joseph Gal. Molecular Chirality in Chemistry and Biology: Historical Milestones. Helvetica Chimica Acta 2013, 96 (9) , 1617-1657. https://doi.org/10.1002/hlca.201300300
    49. Jeffrey I. Seeman. Bonding Beyond Borders: The Nozoe Autograph Books and Other Collections. The Chemical Record 2012, 12 (5) , 517-531. https://doi.org/10.1002/tcr.201200017
    50. . Alkaloids. 2012, 257-287. https://doi.org/10.1002/9781118347300.ch10
    51. Sabine Streller, Klaus Roth. Eine Rinde erobert die Welt. Chemie in unserer Zeit 2012, 46 (4) , 228-247. https://doi.org/10.1002/ciuz.201200593
    52. Tanmoy Chanda, Rajiv Kumar Verma, Maya Shankar Singh. InCl 3 ‐Driven Regioselective Synthesis of Functionalized/Annulated Quinolines: Scope and Limitations. Chemistry – An Asian Journal 2012, 7 (4) , 778-787. https://doi.org/10.1002/asia.201100872
    53. Antonio Garrido Montalban. Quinolines and Isoquinolines. 2011, 299-339. https://doi.org/10.1002/9783527634880.ch9
    54. G. Wayne Craig. The Woodward Research Institute, Robert Burns Woodward (1917–1979) and Chemistry behind the Glass Door. Helvetica Chimica Acta 2011, 94 (6) , 923-946. https://doi.org/10.1002/hlca.201100077
    55. Donald E. Wolf, Karl Folkers. The Preparation of Thiophenes and Tetrahydrothiophenes. 2011, 410-468. https://doi.org/10.1002/0471264180.or006.09
    56. John P. Schaefer, Jordan J. Bloomfield. The D ieckmann Condensation (Including the T horpe‐ Z iegler Condensation). 2011, 1-203. https://doi.org/10.1002/0471264180.or015.01
    57. V. Raja Solomon, Hoyun Lee. Chloroquine and its analogs: A new promise of an old drug for effective and safe cancer therapies. European Journal of Pharmacology 2009, 625 (1-3) , 220-233. https://doi.org/10.1016/j.ejphar.2009.06.063
    58. David Adesanya Ofusori, Sunday Joel Josiah, Abiodun Oladele Ayoka, Emmanuel Oluwole Omotoso, Samson Ayodeji Odukoya. Effect of chronic administration of quinine on the myocardium of mice. Journal of Applied Biomedicine 2008, 6 (4) , 187-193. https://doi.org/10.32725/jab.2008.022
    59. Aaron C. Smith, Robert M. Williams. Rabe Rest in Peace: Confirmation of the Rabe–Kindler Conversion of d‐ Quinotoxine Into Quinine: Experimental Affirmation of the Woodward–Doering Formal Total Synthesis of Quinine. Angewandte Chemie 2008, 120 (9) , 1760-1764. https://doi.org/10.1002/ange.200705421
    60. Aaron C. Smith, Robert M. Williams. Rabe Rest in Peace: Confirmation of the Rabe–Kindler Conversion of d‐ Quinotoxine Into Quinine: Experimental Affirmation of the Woodward–Doering Formal Total Synthesis of Quinine. Angewandte Chemie International Edition 2008, 47 (9) , 1736-1740. https://doi.org/10.1002/anie.200705421
    61. Johann Mulzer. Organische Totalsynthese – Quo vadis?. Nachrichten aus der Chemie 2007, 55 (7-8) , 731-738. https://doi.org/10.1002/nadc.200746724
    62. Gerhard Quinkert, Holger Wallmeier, Norbert Windhab, Dietmar Reichert. Chemistry and Biology — Historical and Philosophical Aspects. 2007, 3-67. https://doi.org/10.1002/9783527619375.ch1
    63. Jeffrey I. Seeman. Die Woodward‐Doering‐/Rabe‐Kindler‐Totalsynthese von Chinin: ein Mythos?. Angewandte Chemie 2007, 119 (9) , 1400-1435. https://doi.org/10.1002/ange.200601551
    64. Jeffrey I. Seeman. The Woodward–Doering/Rabe–Kindler Total Synthesis of Quinine: Setting the Record Straight. Angewandte Chemie International Edition 2007, 46 (9) , 1378-1413. https://doi.org/10.1002/anie.200601551
    65. K. C. Nicolaou, Scott A. Snyder. Die Jagd auf Moleküle, die nie existiert haben: Falsch zugeordnete Naturstoffstrukturen und die Rolle der chemischen Synthese in der modernen Strukturaufklärung. Angewandte Chemie 2005, 117 (7) , 1036-1069. https://doi.org/10.1002/ange.200460864
    66. K. C. Nicolaou, Scott A. Snyder. Chasing Molecules That Were Never There: Misassigned Natural Products and the Role of Chemical Synthesis in Modern Structure Elucidation. Angewandte Chemie International Edition 2005, 44 (7) , 1012-1044. https://doi.org/10.1002/anie.200460864
    67. Teodoro S. Kaufman, Edmundo A. Rúveda. Die Jagd auf Chinin: Etappenerfolge und Gesamtsiege. Angewandte Chemie 2005, 117 (6) , 876-907. https://doi.org/10.1002/ange.200400663
    68. Teodoro S. Kaufman, Edmundo A. Rúveda. The Quest for Quinine: Those Who Won the Battles and Those Who Won the War. Angewandte Chemie International Edition 2005, 44 (6) , 854-885. https://doi.org/10.1002/anie.200400663
    69. Dee Ann Casteel. Antimalarial Agents. 2003, 919-1031. https://doi.org/10.1002/0471266949.bmc091
    70. Barry Dubinsky, Jeffery B. Press. Skeletal Muscle Relaxants. 2000https://doi.org/10.1002/14356007.a24_209
    71. Fritz Eiden. Ausflug in die Vergangenheit : Chinin und andere Chinaalkaloide 3. Teil : Vom Weg zur Totalsynthese der Chinolin‐Chinaalkaloide über die Herstellung besser wirksamer Malariamittel bis zur Erforschung der Indol‐Chinaalkaloide. Pharmazie in unserer Zeit 1999, 28 (2) , 74-86. https://doi.org/10.1002/pauz.19990280208
    72. Barbara Winter‐Werner, François Diederich, Volker Gramlich. Analogs of Cinchona Alkaloids Incorporating a 9,9′‐Spirobifluorene Moiety. Helvetica Chimica Acta 1996, 79 (5) , 1338-1360. https://doi.org/10.1002/hlca.19960790509
    73. John V. Greenhill. Quinoline Ketones. 1990, 89-516. https://doi.org/10.1002/9780470187043.ch2
    74. C. Nootens, R. Merényi, Z. Janousek, H. G. Viehe. Spin delocalisation in heterocyclic captodative radicals 1,2. Bulletin des Sociétés Chimiques Belges 1988, 97 (11-12) , 1045-1054. https://doi.org/10.1002/bscb.19880971130
    75. Hans Wynberg. Asymmetric Catalysis by Alkaloids. 1986, 87-129. https://doi.org/10.1002/9780470147252.ch2
    76. Desmond M. S. Wheeler. R. B. Woodward und die moderne organische Chemie. Chemie in unserer Zeit 1984, 18 (4) , 109-119. https://doi.org/10.1002/ciuz.19840180402
    77. . ROBERT BURNS WOODWARD 1917–1979. 1982, xi-xviii. https://doi.org/10.1016/B978-0-08-029238-0.50005-1
    78. Hans Fiesselmann, Peter Schipprak. Über Oxythiophencarbonsäureester, I. Mitteil.: Über die Anlagerung von Thioglykolsäureester an Fumarsäure‐, Maleinsäure‐ und Acetylendicarbonsäureester). Chemische Berichte 1954, 87 (6) , 835-841. https://doi.org/10.1002/cber.19540870608
    79. Hans Fiesselmann, Gerhard Pfeiffer. Über Oxythiophencarbonsäureester, III. Mitteil.): Die Einwirkung von Thioglykolsäureester auf β‐Ketosäureester (Mitbearbeitet von Ferdinand Memmel). Chemische Berichte 1954, 87 (6) , 848-856. https://doi.org/10.1002/cber.19540870610
    80. E. Schlittler, Joh. Müller. Eine neue Modifikation der Isochinolinsynthese nach Pomeraz‐Fritsch. Helvetica Chimica Acta 1948, 31 (3) , 914-924. https://doi.org/10.1002/hlca.19480310332
    81. V. Prelog, E. Moor. Versuche zur Herstellung von 3‐Vinyl‐piperidinen. Helvetica Chimica Acta 1945, 28 (1) , 182-188. https://doi.org/10.1002/hlca.660280120
    Download PDF
    Go to Journal of the American Chemical Society
    Get e-Alerts
    Get e-Alerts

    Journal of the American Chemical Society

    Cite this: J. Am. Chem. Soc. 1944, 66, 5, 849
    Click to copy citationCitation copied!
    https://doi.org/10.1021/ja01233a516
    Published May 1, 1944
    Request reuse permissions

    Article Views

    4258

    Altmetric

    -

    Citations

    81
    Learn about these metrics

    Article Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.

    Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.

    The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated.