{{Chembox | ImageFile = TCFH.svg | IUPACName = [chloro(dimethylamino)methylidene]-dimethylazanium hexafluorophosphate | OtherNames = {{ubl|''N'',''N'',''N''’,''N''’-Tetramethylchloroformamidinium hexafluorophosphate|Chloro-''N'',''N'',''N''’,''N''’-tetramethylformamidinium hexafluorophosphate}} | Section1 = {{Chembox Identifiers | CASNo = 94790-35-9 | CASNo_Ref = {{cascite|correct|CAS}} | CASNo1 = 207915-99-9 | CASNo1_Comment = (deleted) | CASNo1_Ref = {{cascite|correct|CAS}} | EC_number = 627-919-5 | DTXSID = DTXSID50451023 | PubChem = 10989639 | ChemSpiderID = 9164834 | SMILES = F[P-](F)(F)(F)(F)F.CN(C)C(Cl)=[N+](C)C | StdInChI = 1S/C5H12ClN2.F6P/c1-7(2)5(6)8(3)4;1-7(2,3,4,5)6/h1-4H3;/q+1;-1 | StdInChIKey = CUKNPSDEURGZCO-UHFFFAOYSA-N }} | Section2 = {{Chembox Properties | C = 5 | H = 12 | F = 6 | N = 2 | Cl = 1 | P = 1 | Appearance = White crystalline solid | MeltingPtC = 100-101 | MeltingPt_ref = <ref>{{cite journal | doi = 10.1021/ol034253j | title = ''S'' -(2-Pyridinyl)-1,1,3,3-Tetramethylthiouronium Hexafluorophosphate. A New Reagent for the Synthesis of 2-Pyridinethiol Esters | date = 2003 | last1 = Scardovi | first1 = Noemi | last2 = Garner | first2 = Philip P. | last3 = Protasiewicz | first3 = John D. | journal = Organic Letters | volume = 5 | issue = 10 | pages = 1633–1635 | pmid = 12735739 }}</ref> }} | Section3 = {{Chembox Hazards | ExternalSDS = [https://www.oakwoodchemical.com/ShowMSDS.aspx?Number=038207 Oakwood] | GHSPictograms = {{GHS07}} | GHSSignalWord = Warning | HPhrases = {{H-phrases|302|315|319|335}} | PPhrases = {{P-phrases|261|301+312|302+352|304+340|305+351+338}} }} }}
'''TCFH''' ('''''N'',''N'',''N''’,''N''’-tetramethylchloroformamidinium hexafluorophosphate''') is an electrophilic amidine reagent used to activate a number of functional groups (such as carboxylic acids) for reaction with nucleophilies. TCFH is most commonly used to activate carboxylic acids for reaction with amines in the context of amide bond formation and peptide synthesis.<ref>{{Cite journal |last=Beutner |first=Gregory L. |last2=Young |first2=Ian S. |date=2026-05-11 |title=TCFH-NMI: An Emerging Method for Amide Bond Formation and Beyond |url=https://pubs.acs.org/doi/abs/10.1021/acs.oprd.6c00060 |journal=Organic Process Research & Development |doi=10.1021/acs.oprd.6c00060 |issn=1083-6160|url-access=subscription }}</ref>
__TOC__
== Preparation == TCFH is commercially available. It may be prepared from tetramethylurea using a chlorinating agent such as oxalyl chloride, thionyl chloride or phosphorus oxychloride followed by a salt metathesis reaction.<ref>{{Cite book |url=https://onlinelibrary.wiley.com/doi/book/10.1002/047084289X |title=Encyclopedia of Reagents for Organic Synthesis |date=2001-04-15 |publisher=Wiley |isbn=978-0-471-93623-7 |edition=1 |language=en |doi=10.1002/047084289x.rn02314}}</ref>
== Uses == TCFH itself is a common reagent used in the preparation of uronium and guanidinium salts used for amide bond formation and peptide synthesis, such as HATU.<ref>{{Cite journal |last1=Carpino |first1=Louis A. |last2=Xia |first2=Jusong |last3=El-Faham |first3=Ayman |date=2004-01-01 |title=3-Hydroxy-4-oxo-3,4-dihydro-5-azabenzo-1,2,3-triazene |url=https://pubs.acs.org/doi/10.1021/jo030017a |journal=The Journal of Organic Chemistry |language=en |volume=69 |issue=1 |pages=54–61 |doi=10.1021/jo030017a |pmid=14703378 |issn=0022-3263|url-access=subscription }}</ref><ref>{{Cite patent|number=WO1994007910A1|title=New reagents for peptide couplings|gdate=1994-04-14|invent1=Carpino|inventor1-first=Louis A.|url=https://patents.google.com/patent/WO1994007910A1/en?oq=WO1994007910}}</ref><ref>{{Cite journal |last1=Carpino |first1=Louis A. |last2=Ferrer |first2=Fernando J. |date=2001-09-01 |title=The 5,6- and 4,5-Benzo Derivatives of 1-Hydroxy-7-azabenzotriazole |url=https://pubs.acs.org/doi/10.1021/ol016063j |journal=Organic Letters |language=en |volume=3 |issue=18 |pages=2793–2795 |doi=10.1021/ol016063j |pmid=11529758 |issn=1523-7060|url-access=subscription }}</ref>
Amide bond formation with TCFH can be performed in a wide range of organic solvents, most commonly acetonitrile, but also water<ref>{{Cite journal |last1=Bailey |first1=J. Daniel |last2=Helbling |first2=Edward |last3=Mankar |first3=Amey |last4=Stirling |first4=Matthew |last5=Hicks |first5=Fred |last6=Leahy |first6=David K. |date=2021-02-01 |title=Beyond organic solvents: synthesis of a 5-HT4 receptor agonist in water |url=https://pubs.rsc.org/en/content/articlelanding/2021/gc/d0gc03316b |journal=Green Chemistry |language=en |volume=23 |issue=2 |pages=788–795 |doi=10.1039/D0GC03316B |issn=1463-9270|url-access=subscription }}</ref> and in the solid state.<ref>{{Cite journal |last1=Dalidovich |first1=Tatsiana |last2=Mishra |first2=Kamini A. |last3=Shalima |first3=Tatsiana |last4=Kudrjašova |first4=Marina |last5=Kananovich |first5=Dzmitry G. |last6=Aav |first6=Riina |date=2020-10-19 |title=Mechanochemical Synthesis of Amides with Uronium-Based Coupling Reagents: A Method for Hexa-amidation of Biotin[6]uril |url=https://pubs.acs.org/doi/10.1021/acssuschemeng.0c05558 |journal=ACS Sustainable Chemistry & Engineering |language=en |volume=8 |issue=41 |pages=15703–15715 |doi=10.1021/acssuschemeng.0c05558 |issn=2168-0485|url-access=subscription }}</ref> Reactions typically require an added Brønsted base, and a wide range can be employed including ''N,N''-diisopropylethylamine (DIPEA). In reactions of carboxylic acids with TCFH and a weakly Lewis basic amine like DIPEA, formation of an acid chloride or anhydride as the active acylating agent occurs.<ref>{{Cite journal |last1=Tulla-Puche |first1=Judit |last2=Torres |first2=Ángela |last3=Calvo |first3=Pilar |last4=Royo |first4=Miriam |last5=Albericio |first5=Fernando |date=2008-10-15 |title=N,N,N′,N′ -Tetramethylchloroformamidinium Hexafluorophosphate (TCFH), a Powerful Coupling Reagent for Bioconjugation |url=https://pubs.acs.org/doi/10.1021/bc8002327 |journal=Bioconjugate Chemistry |language=en |volume=19 |issue=10 |pages=1968–1971 |doi=10.1021/bc8002327 |pmid=18803415 |issn=1043-1802|url-access=subscription }}</ref> Use of ''N''-methylimidazole (NMI) as a base, with both Brønsted and Lewis basic properties, provides some unique advantages. Reactions of carboxylic acids with TCFH and a strongly Lewis basic amine like NMI lead to ''in situ'' formation of an ''N''-acyl imidazolium ion (NAI) as the active acylating agent. center|frameless|364x364px|TCFH Mechanism These strongly electrophilic NAIs<ref>{{Cite journal |last1=Wolfenden |first1=Richard |last2=Jencks |first2=William P. |date=1961 |title=Acetyl Transfer Reactions of 1-Acetyl-3-methylimidazolium Chloride 1 |url=https://pubs.acs.org/doi/abs/10.1021/ja01482a023 |journal=Journal of the American Chemical Society |language=en |volume=83 |issue=21 |pages=4390–4393 |doi=10.1021/ja01482a023 |bibcode=1961JAChS..83.4390W |issn=0002-7863|url-access=subscription }}</ref><ref>{{Cite journal |last1=Dadali |first1=V.A. |last2=Zubareva |first2=T.M. |last3=Litvinenko |first3=L.M. |last4=Simanenko |first4=Y.S. |date=1984 |title=Effect of Structural Factors on the Kinetics of Formation and Reactivity of the Intermediate Product in Acyl Transfer Reaction Catalyzed by Imidazoles |journal=J. Org. Chem. USSR |volume=20 |pages=1542–1551}}</ref> allow for reactions with a wide range of nitrogen nucleophiles, including hindered and electron-deficient amines.<ref>{{Cite journal |last1=Beutner |first1=Gregory L. |last2=Young |first2=Ian S. |last3=Davies |first3=Merrill L. |last4=Hickey |first4=Matthew R. |last5=Park |first5=Hyunsoo |last6=Stevens |first6=Jason M. |last7=Ye |first7=Qingmei |date=2018-07-20 |title=TCFH–NMI: Direct Access to N -Acyl Imidazoliums for Challenging Amide Bond Formations |url=https://pubs.acs.org/doi/10.1021/acs.orglett.8b01591 |journal=Organic Letters |language=en |volume=20 |issue=14 |pages=4218–4222 |doi=10.1021/acs.orglett.8b01591 |pmid=29956545 |issn=1523-7060|url-access=subscription |doi-access=free }}</ref> An added benefit of the use of NMI as the base, due to its low p''K''<sub>a</sub>(H<sub>2</sub>O) of 7,<ref>{{Cite journal |last1=Bender |first1=Myron L. |last2=Turnquest |first2=Byron W. |date=1957 |title=General Basic Catalysis of Ester Hydrolysis and Its Relationship to Enzymatic Hydrolysis 1 |url=https://pubs.acs.org/doi/abs/10.1021/ja01564a035 |journal=Journal of the American Chemical Society |language=en |volume=79 |issue=7 |pages=1656–1662 |doi=10.1021/ja01564a035 |bibcode=1957JAChS..79.1656B |issn=0002-7863|url-access=subscription }}</ref> is that the epimerization of labile stereogenic centers is minimized. The reaction by-products have high water solubility, facilitating reaction workup and isolation. center|frameless|362x362px TCFH can also be used in other reactions involving activation of carboxylic acids from reactions with oxygen-, sulfur- and carbon-nucleophiles for the preparation of esters, thioesters and ketones.<ref>{{Cite journal |last1=Luis |first1=Nathaniel R. |last2=Chung |first2=Kasey K. |last3=Hickey |first3=Matthew R. |last4=Lin |first4=Ziqing |last5=Beutner |first5=Gregory L. |last6=Vosburg |first6=David A. |date=2024-04-12 |title=Beyond Amide Bond Formation: TCFH as a Reagent for Esterification |url=https://pubs.acs.org/doi/10.1021/acs.orglett.3c01611 |journal=Organic Letters |language=en |volume=26 |issue=14 |pages=2745–2750 |doi=10.1021/acs.orglett.3c01611 |pmid=37364890 |issn=1523-7060|url-access=subscription }}</ref><ref>{{Cite journal |last1=Ho |first1=Johnson H. |last2=Miller |first2=Grant H. |last3=Chung |first3=Kasey K. |last4=Neibert |first4=Sydney D. |last5=Beutner |first5=Gregory L. |last6=Vosburg |first6=David A. |date=2024-10-07 |title=TCFH–NMI Ketone Synthesis Inspired by Nucleophilicity Scales |url=https://pubs.acs.org/doi/10.1021/acs.orglett.4c03363 |journal=Organic Letters |volume=26 |issue=41 |pages=8904–8909 |language=en |doi=10.1021/acs.orglett.4c03363 |pmid=39374118 |issn=1523-7060|url-access=subscription }}</ref> Extending beyond reactions with carboxylic acids, TCFH has been shown to be an activator for other oxygen centered nucleophiles, including heterocyclic alcohols, ketooximes, and even alcohols.<ref>{{Cite journal |last1=George |first1=David T. |last2=Williams |first2=Michael J. |last3=Beutner |first3=Gregory L. |date=2023 |title=Safety as a Factor in Reaction Development: Considerations of Sensitization Potential with Amide Bond Forming Reagents |url=https://onlinelibrary.wiley.com/doi/10.1002/hlca.202300140 |journal=Helvetica Chimica Acta |language=en |volume=106 |issue=11 |doi=10.1002/hlca.202300140 |bibcode=2023HChAc.106E0140G |issn=0018-019X|url-access=subscription }}</ref><ref>{{Cite journal |last1=Lee |first1=Su Eun |last2=Kim |first2=Youngsoo |last3=Lee |first3=Yong Ho |last4=Lim |first4=Hee Nam |date=2024-05-03 |title=C–C Bond Cleavage-Induced C- to N-Acyl Transfer for Synthesis of Amides |url=https://pubs.acs.org/doi/10.1021/acs.orglett.4c01154 |journal=Organic Letters |language=en |volume=26 |issue=17 |pages=3646–3651 |doi=10.1021/acs.orglett.4c01154 |pmid=38656111 |issn=1523-7060|url-access=subscription}}</ref> Reactivity with sulfur centered nucleophiles like thioureas has also been demonstrated. center|frameless|880x880px|Uses of TCFH
== Safety == TCFH does not irritate skin but is a potent eye irritant.<ref>{{Cite journal |last1=Graham |first1=Jessica C. |last2=Trejo-Martin |first2=Alejandra |last3=Chilton |first3=Martyn L. |last4=Kostal |first4=Jakub |last5=Bercu |first5=Joel |last6=Beutner |first6=Gregory L. |last7=Bruen |first7=Uma S. |last8=Dolan |first8=David G. |last9=Gomez |first9=Stephen |last10=Hillegass |first10=Jedd |last11=Nicolette |first11=John |last12=Schmitz |first12=Matthew |date=2022-06-20 |title=An Evaluation of the Occupational Health Hazards of Peptide Couplers |journal=Chemical Research in Toxicology |language=en |volume=35 |issue=6 |pages=1011–1022 |doi=10.1021/acs.chemrestox.2c00031 |issn=0893-228X |pmc=9214767 |pmid=35532537}}</ref> The sensitization potential of TCFH was shown to be low compared to other amide bond forming agents, which can be used in the context of peptide synthesis (it is non-sensitizing at 1% in the local lymph node assay according to OECD 429<ref>{{Cite book |last=OECD |url=https://www.oecd-ilibrary.org/environment/test-no-429-skin-sensitisation_9789264071100-en |title=Test No. 429: Skin Sensitisation: Local Lymph Node Assay |date=2010 |publisher=Organisation for Economic Co-operation and Development |location=Paris |language=en}}</ref>). The major by-product of using TCFH is tetramethylurea, which has demonstrated teratogenic activity in several laboratory animal species.<ref>{{Cite book |url=https://onlinelibrary.wiley.com/doi/book/10.1002/3527600418 |title=The MAK-Collection for Occupational Health and Safety: Annual Thresholds and Classifications for the Workplace |date=2002 |publisher=Wiley |isbn=978-3-527-60041-0 |editor-last=Deutsche Forschungsgemeinschaft |edition=1 |language=de |doi=10.1002/3527600418.mb63222d0007 |editor-last2=Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area}}</ref>
==References== {{Reflist}}
Category:Reagents for organic chemistry Category:Peptide coupling reagents Category:Amidines Category:Hexafluorophosphates