:N,N'-Dicyclohexylcarbodiimide

The C−N=C=N−C core of carbodiimides (N=C=N) is linear, being related to the structure of allene. The molecule has idealized C₂ symmetry.

The N=C=N moiety gives characteristic IR spectroscopic signature at 2117 cm⁻¹. The ¹⁵N NMR spectrum shows a characteristic shift of 275 ppm upfield of nitric acid and the ¹³C NMR spectrum features a peak at about 139 ppm downfield from TMS.{{cite journal |author1=Yavari, I. |author2=Roberts, J. D. | title = Nitrogen-15 Nuclear Magnetic Resonance Spectroscopy. Carbodiimides | journal = Journal of Organic Chemistry | year = 1978 | volume = 43 | issue = 25 | pages = 4689–4690 | doi = 10.1021/jo00419a001|url=https://authors.library.caltech.edu/60866/2/jo00419a001_si_001.pdf }}

DCC is produced by the decarboxylation of cyclohexylisocyanate using phosphine oxides as a catalyst:{{cite journal |doi=10.15227/orgsyn.043.0031|title=Diphenylcarbodiimide|journal=Organic Syntheses|year=1963|volume=43|page=31|first1=T. W.|last1=Campbell|first2=J. J.|last2=Monagle}}

:2 C₆H₁₁NCO → (C₆H₁₁N)₂C + CO₂

Alternative catalysts for this conversion include the highly nucleophilic OP(MeNCH₂CH₂)₃N.{{cite journal |author1=Tang, J. |author2=Mohan, T. |author3=Verkade, J. G. | title = Selective and Efficient Syntheses of Perhydro-1,3,5-triazine-2,4,6-triones and Carbodiimides from Isocyanates Using ZP(MeNCH₂CH₂)₃N Catalysts | journal = Journal of Organic Chemistry | year = 1994 | volume = 59 | issue = 17 | pages = 4931–4938 | doi = 10.1021/jo00096a041}}

Of academic interest, palladium acetate, iodine, and oxygen can be used to couple cyclohexyl amine and cyclohexyl isocyanide.{{cite journal |author1=Pri-Bar, I. |author2=Schwartz, J. | title = N,N-Dialkylcarbodiimide Synthesis by Palladium-Catalysed Coupling of Amines with Isonitriles | journal = Chemical Communications | year = 1997 | volume = 1997 | issue = 4 | pages = 347–348 | doi = 10.1039/a606012i}} Yields of up to 67% have been achieved using this route:

: C₆H₁₁NC + C₆H₁₁NH₂ + O₂ → (C₆H₁₁N)₂C + H₂O

DCC has also been prepared from dicyclohexylurea using a phase transfer catalyst. The disubstituted urea, arenesulfonyl chloride, and potassium carbonate react in toluene in the presence of benzyl triethylammonium chloride to give DCC in 50% yield.{{cite journal |author1=Jászay, Z. M. |author2=Petneházy, I. |author3=Töke, L. |author4=Szajáni, B. | title = Preparation of Carbodiimides Using Phase-Transfer Catalysis | journal = Synthesis | year = 1987 | volume = 1987 | issue = 5 | pages = 520–523 | doi = 10.1055/s-1987-27992}}

:file:DCC synthesis.svg{{clear left}}

DCC is a dehydrating agent for the preparation of amides, ketones, and nitriles. In these reactions, DCC hydrates to form dicyclohexylurea (DCU), a compound that is nearly insoluble in most organic solvents and insoluble in water. The majority of the DCU is thus readily removed by filtration, although the last traces can be difficult to eliminate from non-polar products. DCC can also be used to invert secondary alcohols. In the Steglich esterification, alcohols, including even some tertiary alcohols, can be esterified using a carboxylic acid in the presence of DCC and a catalytic amount of DMAP.{{cite journal | title = Esterification of Carboxylic Acids with Dicyclohexylcarbodiimide/4-Dimethylaminopyridine: Tert-Butyl Ethyl Fumarate |author1=Neises, B. |author2=Steglich, W. |journal=Organic Syntheses | year = 1985 | volume = 63 | page = 183 |doi=10.15227/orgsyn.063.0183}}

In protein synthesis (such as Fmoc solid-state synthesizers), the N-terminus is often used as the attachment site on which the amino acid monomers are added. To enhance the electrophilicity of carboxylate group, the negatively charged oxygen must first be "activated" into a better leaving group. DCC is used for this purpose. The negatively charged oxygen will act as a nucleophile, attacking the central carbon in DCC. DCC is temporarily attached to the former carboxylate group forming a highly electrophilic intermediate, making nucleophilic attack by the terminal amino group on the growing peptide more efficient.

In combination with dimethyl sulfoxide (DMSO), DCC affects the Pfitzner–Moffatt oxidation.{{cite journal|title=Cholane-24-al|author=John G. Moffatt|journal=Org. Synth.|year=1967|volume=47|page=25|doi=10.15227/orgsyn.047.0025}} This procedure is used for the oxidation of alcohols to aldehydes and ketones. Unlike metal-mediated oxidations, such as the Jones oxidation, the reaction conditions are sufficiently mild to avoid over-oxidation of aldehydes to carboxylic acids. Generally, three equivalents of DCC and 0.5 equivalents of proton source in DMSO are allowed to react overnight at room temperature. The reaction is quenched with acid.

• Reaction of an acid with hydrogen peroxide in presence of DCC leads to formation of peroxide linkage.
• Alcohols can also be dehydrated using DCC. This reaction proceeds by first giving the O-acylurea intermediate which is then hydrogenolyzed to produce the corresponding alkene:

:RCHOHCH₂R′ + (C₆H₁₁N)₂C → RCH=CHR′ + (C₆H₁₁NH)₂CO

• Secondary alcohols can be stereochemically inverted by formation of a formyl ester followed by saponification. The secondary alcohol is mixed directly with DCC, formic acid, and a strong base such as sodium methoxide.
• In the presence of DMAP, DCC self-condenses two molecules of phenylacetic acid and its substituted derivatives to produce a bisbenzyl ketone.{{cite journal |last1=Bhandari |first1=Sumita |last2=Ray |first2=Suprabhat |date=17 Jun 1997 |title=A Novel Synthesis of Bisbenzyl Ketones by DCC Induced Condensation of Phenylacetic Acid |journal=Synthetic Communications |volume=28 |issue=5 |pages=765–771 |doi=10.1080/00032719808006472}}

DCC is a classical inhibitor of ATP synthase.{{cite journal |vauthors=Hong S, Pedersen PL | year = 2008 | title = ATP synthase and the actions of inhibitors utilized to study its roles in human health, disease, and other scientific areas | journal = Microbiol Mol Biol Rev | volume = 72 | issue = 4 | pages = 590–641 | doi = 10.1128/MMBR.00016-08 | pmid = 19052322 | pmc = 2593570}} DCC inhibits ATP synthase by binding to one of the c subunits and causing steric hindrance of the rotation of the F_O subunit.{{cite journal |vauthors=Toei M, Noji H | year = 2013 | title = Single-molecule analysis of F₀F₁-ATP synthase inhibited by N,N-dicyclohexylcarbodiimide | journal = J Biol Chem | volume = 288 | issue = 36 | pages = 25717–25726 | doi = 10.1074/jbc.M113.482455 | pmid = 23893417 | pmc = 3764779| doi-access = free }}

DCC often causes rashes. In vivo dermal sensitization studies according to OECD 429{{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}} confirmed DCC is a strong skin sensitizer, showing a response at 0.03 wt% in the Local Lymph Node Assay (LLNA) placing it in Globally Harmonized System of Classification and Labelling of Chemicals (GHS) Dermal Sensitization Category 1A.{{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}} Thermal hazard analysis by differential scanning calorimetry (DSC) shows DCC poses minimal explosion risks.{{Cite journal |last1=Sperry |first1=Jeffrey B. |last2=Minteer |first2=Christopher J. |last3=Tao |first3=JingYa |last4=Johnson |first4=Rebecca |last5=Duzguner |first5=Remzi |last6=Hawksworth |first6=Michael |last7=Oke |first7=Samantha |last8=Richardson |first8=Paul F. |last9=Barnhart |first9=Richard |last10=Bill |first10=David R. |last11=Giusto |first11=Robert A. |last12=Weaver |first12=John D. |date=2018-09-21 |title=Thermal Stability Assessment of Peptide Coupling Reagents Commonly Used in Pharmaceutical Manufacturing |url=https://pubs.acs.org/doi/10.1021/acs.oprd.8b00193 |journal=Organic Process Research & Development |language=en |volume=22 |issue=9 |pages=1262–1275 |doi=10.1021/acs.oprd.8b00193 |issn=1083-6160|url-access=subscription }}

• Carbodiimide

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• An excellent illustration of this mechanism can be found here: [http://chemistry2.csudh.edu/rpendarvis/AmAcSeqSyn.html].

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Category:Dehydrating agents

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