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While DMF is already regulated in Europe, TFA \u2013 a member of the polyfluoroalkyl substances (PFAS) family \u2013 is expected to face similar restrictions soon. These compounds break down slowly and pose risks to human health and the environment. Herein, the use of the so\u2010called \u201cgreen acid par excellence\u201d, methanesulfonic acid (MSA), in substitution of TFA is discussed. As MSA is stronger than TFA, it is diluted with a solvent for use. The effectivity of MSA depends on the solvents used. When dichloromethane (DCM) is used, 1.5\u2009% MSA removes all side\u2010chain protecting groups, except the trityl (Trt) group of His. In the presence of acetic acid (AcOH) and dimethylcarbonate (DMC), more concentrated solutions of MSA (8\u201316\u2009%) are required. The removal of the Trt group of Asn\/Gln continues to be a challenge even with these solutions, and aspartimide formation can occur in Asp\u2010containing peptides.<\/jats:p>","DOI":"10.1002\/cssc.202402752","type":"journal-article","created":{"date-parts":[[2025,2,6]],"date-time":"2025-02-06T11:09:24Z","timestamp":1738840164000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Scope and Limitations of the Use of Methanesulfonic Acid (MSA) as a Green Acid for Global Deprotection in Solid\u2010Phase Peptide Synthesis"],"prefix":"10.1002","volume":"18","author":[{"given":"Giovanni","family":"Vivenzio","sequence":"first","affiliation":[{"name":"Peptide Science Laboratory School of Chemistry and Physics University of KwaZulu-Natal  Durban 4001 South Africa"},{"name":"Department of Pharmacy University of Salerno  84084- Fisciano Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sikabwe","family":"Noki","sequence":"additional","affiliation":[{"name":"Peptide Science Laboratory School of Chemistry and Physics University of KwaZulu-Natal  Durban 4001 South Africa"},{"name":"School of Laboratory Medicine and Medical Sciences College of Health Sciences University of KwaZulu-Natal  Durban 4041 South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amit","family":"Chakraborty","sequence":"additional","affiliation":[{"name":"Peptide Science Laboratory School of Chemistry and Physics University of KwaZulu-Natal  Durban 4001 South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Lopez","sequence":"additional","affiliation":[{"name":"Novartis Pharma AG, 4056-  Basel Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beatriz G","family":"de la Torre","sequence":"additional","affiliation":[{"name":"Novartis Pharma AG, 4056-  Basel Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8946-0462","authenticated-orcid":false,"given":"Fernando","family":"Albericio","sequence":"additional","affiliation":[{"name":"Peptide Science Laboratory School of Chemistry and Physics University of KwaZulu-Natal  Durban 4001 South Africa"},{"name":"Department of Organic Chemistry University of Barcelona  Mart\u00ed i Franqu\u00e9s 1\u201311 08028- Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,2,21]]},"reference":[{"key":"e_1_2_7_1_1","doi-asserted-by":"publisher","DOI":"10.3390\/ph17020243"},{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-022-00904-4"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41573-020-00135-8"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja00897a025"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1039\/C9GC03982A"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1021\/op060170h"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.joc.3c01494"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1039\/C6GC00611F"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1021\/ie402410w"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/cssc.202301639"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1021\/acssuschemeng.9b01766"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1039\/C8GC03778G"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1021\/acssuschemeng.6b01765"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1039\/C4OB02046D"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00726-015-2095-x"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1021\/acssuschemeng.8b01531"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tetlet.2017.06.058"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1039\/C7GC00247E"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40508-016-0051-z"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.oprd.7b00389"},{"key":"e_1_2_7_21_1","first-page":"544","volume":"14","author":"Kumar A.","year":"2021","journal-title":"Green Chem. 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