Carbodiimide

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General structure of trans-carbodiimides: The core functional group is shown in blue with attached R groups Carbodiimides General Structure V.1.svg
General structure of trans-carbodiimides: The core functional group is shown in blue with attached R groups

In organic chemistry, a carbodiimide (systematic IUPAC name: methanediimine [1] ) is a functional group with the formula RN=C=NR. On Earth they are exclusively synthetic, but in interstellar space the parent compound HN=C=NH has been detected by its maser emissions. [2]

Contents

A well known carbodiimide is dicyclohexylcarbodiimide, which is used in peptide synthesis. [3] Dialkylcarbodiimides are stable. Some diaryl derivatives tend to convert to dimers and polymers upon standing at room temperature, though this mostly occurs with low melting point carbodiimides that are liquids at room temperature. [4] Solid diaryl carbodiimides are more stable, but can slowly undergo hydrolysis in the presence of water over time.

Structure and bonding

Structure of C(NCHPh2)2 as determined by X-ray crystallography (color scheme: gray = C, blue = N) CSD CIF PMCBIM.jpg
Structure of C(NCHPh2)2 as determined by X-ray crystallography (color scheme: gray = C, blue = N)

From the perspective of bonding, carbodiimides are isoelectronic with carbon dioxide. Three principal resonance structures describe carbodiimides:

RN=C=NR ↔ RN+≡C-N−R ↔ RN−-C≡N+R

The N=C=N core is relatively linear and the C-N=C angles approach 120°. In the case of C(NCHPh2)2, the central N=C=N angle is 170° and the C-N=C angles are within 1° of 126°. [5] The C=N distances are short, nearly 120 pm, as is characteristic of double bonds. Carbodiimides are chiral, possessing C2-symmetry and therefore axial chirality. [6] However, due to the low energy barrier to the molecule rotating and thereby converting quickly between its isomers, the actual isolation of one optical isomer of a carbodiimide is extremely difficult. It has been demonstrated at least once, in the case of conformationally restricted cyclic carbodiimides; though there are other reports of one-handed axially chiral carbodiimides, their validity has since been called into question on experimental and computational grounds. [7] [8]

The parent compound, methanediimine, (HN=C=NH), is a tautomer of cyanamide.

Synthesis

From thioureas and ureas

A classic route to carbodiimides involves dehydrosulfurization of thioureas. A typical reagent for this process is mercuric oxide: [9]

(R(H)N)2CS + HgO → (RN)2C + HgS + H2O

This reaction can often be conducted as stated, even though carbodiimides react with water. In some cases, a dehydrating agent is added to the reaction mixture.

The dehydration of N,N'-dialkylureas gives carbodiimides:

(R(H)N)2CO → (RN)2C + H2O

Phosphorus pentoxide [10] and p-Toluenesulfonyl chloride have been used as a dehydrating agents. [11] [12]

From isocyanates

Isocyanates can be converted to carbodiimides with loss of carbon dioxide: [13] [4]

2 RN=C=O → (RN)2C + CO2

The reaction is catalyzed by phosphine oxides. This reaction is reversible. [9]

Reactions

Compared to other heteroallenes, carbodiimides are very weak electrophiles and only react with nucleophiles in the presence of catalysts, such as acids. [14] In this way, guanidines can be prepared. [3] As weak bases, carbodiimides bind to Lewis acids to give adducts. [9]

Moffatt oxidation

Carbodiimides are reagents for the Moffatt oxidation, a protocol for conversion of an alcohol to a carbonyl (ketone or aldehyde) using dimethyl sulfoxide as the oxidizing agent: [15]

(CH3)2SO + (CyN)2C + R2CHOH → (CH3)2S + (CyNH)2CO + R2C=O

Typically the sulfoxide and diimide are used in excess. [16] The reaction generates dimethyl sulfide and a urea as byproducts.

Coupling agents

In organic synthesis, compounds containing the carbodiimide functionality are used as dehydration agents. Specifically they are often used to convert carboxylic acids to amides or esters. Additives, such as N-hydroxybenzotriazole or N-hydroxysuccinimide, are often added to increase yields and decrease side reactions.

Amide coupling utilizing a carbodiimide Carbodiimide Amide Coupling Scheme.png
Amide coupling utilizing a carbodiimide

Polycarbodiimides can also be used as crosslinkers for aqueous resins, such as polyurethane dispersions or acrylic dispersion. Here the polycarbodiimide reacts with carboxylic acids, whose functional groups are often present in such aqueous resins, to form N-acyl urea. The result is the formation of covalent bonds between the polymer chains, making them crosslinked. [17] [18]

Amide formation pathway

The formation of an amide using a carbodiimide is a common reaction, but carries the risk of several side reactions. The acid 1 will react with the carbodiimide to produce the key intermediate: the O-acylisourea 2, which can be viewed as a carboxylic ester with an activated leaving group. The O-acylisourea will react with amines to give the desired amide 3 and urea 4.

The possible reactions of the O-acylisourea 2 produce both desired and undesired products. The O-acylisourea 2 can react with an additional carboxylic acid 1 to give an acid anhydride 5, which can react further to give the amide 3. The main undesired reaction pathway involves the rearrangement of the O-acylisourea 2 to the stable N-acylurea 6. The use of solvents with low dielectric constants such as dichloromethane or chloroform can minimize this side reaction. [19]

The reaction mechanism of amide formation using a carbodiimide Carbodiimide Mechanism.png
The reaction mechanism of amide formation using a carbodiimide

Examples

DCC

Structure of N,N'-dicyclohexylcarbodiimide DCC Structure.png
Structure of N,N'-dicyclohexylcarbodiimide

DCC (acronym for N,N'-dicyclohexylcarbodiimide) was one of the first carbodiimides developed as a reagent. It is widely used for amide and ester formation, especially for solid-phase synthesis of peptides. DCC has achieved popularity mainly because of its high-yielding amide coupling reactions and the fact that it is quite inexpensive.

However, DCC does have some serious drawbacks, and its use is often avoided for several reasons:

  1. The byproduct N,N'-dicyclohexylurea is mostly removed by filtration, but trace impurities can be difficult to remove. It is incompatible with traditional solid-phase peptide synthesis.
  2. DCC is a potent allergen, and repeated contact with skin increases the probability of sensitization to the compound. Clinical reports of individuals who cannot enter rooms where peptide coupling agents are used have been reported.

DIC

Structure of N,N'-diisopropylcarbodiimide DIC Structure.png
Structure of N,N'-diisopropylcarbodiimide

In contrast to DCC, DIC (N,N'-diisopropylcarbodiimide) is a liquid. Its hydrolysis product, N,N'-diisopropylurea, is soluble in organic solvents.

EDC

EDC is a water-soluble carbodiimide reagent used for a wide range of purposes. Apart from uses similar to those of DCC and DIC, it is also used for various biochemical purposes as a crosslinker or chemical probe.

CMCT or CMC

1-cyclohexyl-(2-morpholinoethyl)carbodiimide metho-p-toluene sulfonate is a carbodiimide developed for the chemical probing of RNA structure in biochemistry.

See also

Related Research Articles

<span class="mw-page-title-main">Amide</span> Organic compounds of the form RC(=O)NR′R″

In organic chemistry, an amide, also known as an organic amide or a carboxamide, is a compound with the general formula R−C(=O)−NR′R″, where R, R', and R″ represent any group, typically organyl groups or hydrogen atoms. The amide group is called a peptide bond when it is part of the main chain of a protein, and an isopeptide bond when it occurs in a side chain, as in asparagine and glutamine. It can be viewed as a derivative of a carboxylic acid with the hydroxyl group replaced by an amine group ; or, equivalently, an acyl (alkanoyl) group joined to an amine group.

<span class="mw-page-title-main">Ester</span> Compound derived from an acid

In chemistry, an ester is a functional group derived from an acid in which the hydrogen atom (H) of at least one acidic hydroxyl group of that acid is replaced by an organyl group. Analogues derived from oxygen replaced by other chalcogens belong to the ester category as well. According to some authors, organyl derivatives of acidic hydrogen of other acids are esters as well, but not according to the IUPAC.

<span class="mw-page-title-main">Ketene</span> Organic compound of the form >C=C=O

In organic chemistry, a ketene is an organic compound of the form RR'C=C=O, where R and R' are two arbitrary monovalent chemical groups. The name may also refer to the specific compound ethenone H2C=C=O, the simplest ketene.

In organic chemistry, the Swern oxidation, named after Daniel Swern, is a chemical reaction whereby a primary or secondary alcohol is oxidized to an aldehyde or ketone using oxalyl chloride, dimethyl sulfoxide (DMSO) and an organic base, such as triethylamine. It is one of the many oxidation reactions commonly referred to as 'activated DMSO' oxidations. The reaction is known for its mild character and wide tolerance of functional groups.

<span class="mw-page-title-main">Thioester</span> Organosulfur compounds of the form R–SC(=O)–R’

In organic chemistry, thioesters are organosulfur compounds with the molecular structure R−C(=O)−S−R’. They are analogous to carboxylate esters with the sulfur in the thioester replacing oxygen in the carboxylate ester, as implied by the thio- prefix. They are the product of esterification of a carboxylic acid with a thiol. In biochemistry, the best-known thioesters are derivatives of coenzyme A, e.g., acetyl-CoA. The R and R' represent organyl groups, or H in the case of R.

<span class="mw-page-title-main">Organolithium reagent</span> Chemical compounds containing C–Li bonds

In organometallic chemistry, organolithium reagents are chemical compounds that contain carbon–lithium (C–Li) bonds. These reagents are important in organic synthesis, and are frequently used to transfer the organic group or the lithium atom to the substrates in synthetic steps, through nucleophilic addition or simple deprotonation. Organolithium reagents are used in industry as an initiator for anionic polymerization, which leads to the production of various elastomers. They have also been applied in asymmetric synthesis in the pharmaceutical industry. Due to the large difference in electronegativity between the carbon atom and the lithium atom, the C−Li bond is highly ionic. Owing to the polar nature of the C−Li bond, organolithium reagents are good nucleophiles and strong bases. For laboratory organic synthesis, many organolithium reagents are commercially available in solution form. These reagents are highly reactive, and are sometimes pyrophoric.

In organic chemistry, a nitrile is any organic compound that has a −C≡N functional group. The name of the compound is composed of a base, which includes the carbon of the −C≡N, suffixed with "nitrile", so for example CH3CH2C≡N is called "propionitrile". The prefix cyano- is used interchangeably with the term nitrile in industrial literature. Nitriles are found in many useful compounds, including methyl cyanoacrylate, used in super glue, and nitrile rubber, a nitrile-containing polymer used in latex-free laboratory and medical gloves. Nitrile rubber is also widely used as automotive and other seals since it is resistant to fuels and oils. Organic compounds containing multiple nitrile groups are known as cyanocarbons.

<span class="mw-page-title-main">Peptide synthesis</span> Production of peptides

In organic chemistry, peptide synthesis is the production of peptides, compounds where multiple amino acids are linked via amide bonds, also known as peptide bonds. Peptides are chemically synthesized by the condensation reaction of the carboxyl group of one amino acid to the amino group of another. Protecting group strategies are usually necessary to prevent undesirable side reactions with the various amino acid side chains. Chemical peptide synthesis most commonly starts at the carboxyl end of the peptide (C-terminus), and proceeds toward the amino-terminus (N-terminus). Protein biosynthesis in living organisms occurs in the opposite direction.

<i>N</i>,<i>N</i>-Dicyclohexylcarbodiimide Chemical compound

N,N′-Dicyclohexylcarbodiimide (DCC or DCCD) is an organic compound with the chemical formula (C6H11N)2C. It is a waxy white solid with a sweet odor. Its primary use is to couple amino acids during artificial peptide synthesis. The low melting point of this material allows it to be melted for easy handling. It is highly soluble in dichloromethane, tetrahydrofuran, acetonitrile and dimethylformamide, but insoluble in water.

<i>N</i>,<i>N</i>-Diisopropylethylamine Chemical compound

N,N-Diisopropylethylamine, or Hünig's base, is an organic compound that is a tertiary amine. It is named after the German chemist Siegfried Hünig. It is used in organic chemistry as a non-nucleophilic base. It is commonly abbreviated as DIPEA,DIEA, or i-Pr2NEt.

<span class="mw-page-title-main">Chiral auxiliary</span> Stereogenic group placed on a molecule to encourage stereoselectivity in reactions

In stereochemistry, a chiral auxiliary is a stereogenic group or unit that is temporarily incorporated into an organic compound in order to control the stereochemical outcome of the synthesis. The chirality present in the auxiliary can bias the stereoselectivity of one or more subsequent reactions. The auxiliary can then be typically recovered for future use.

The Weinreb ketone synthesis or Weinreb–Nahm ketone synthesis is a chemical reaction used in organic chemistry to make carbon–carbon bonds. It was discovered in 1981 by Steven M. Weinreb and Steven Nahm as a method to synthesize ketones. The original reaction involved two subsequent nucleophilic acyl substitutions: the conversion of an acid chloride with N,O-Dimethylhydroxylamine, to form a Weinreb–Nahm amide, and subsequent treatment of this species with an organometallic reagent such as a Grignard reagent or organolithium reagent. Nahm and Weinreb also reported the synthesis of aldehydes by reduction of the amide with an excess of lithium aluminum hydride.

Mosher's acid, or α-methoxy-α-trifluoromethylphenylacetic acid (MTPA) is a carboxylic acid which was first used by Harry Stone Mosher as a chiral derivatizing agent. It is a chiral molecule, consisting of R and S enantiomers.

<i>N</i>-Hydroxysuccinimide Chemical compound

N-Hydroxysuccinimide (NHS) is an organic compound with the formula (CH2CO)2NOH. It is a white solid that is used as a reagent for preparing active esters in peptide synthesis. It can be synthesized by heating succinic anhydride with hydroxylamine or hydroxylamine hydrochloride.

<span class="mw-page-title-main">1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide</span> Chemical compound

1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide is a water-soluble carbodiimide usually handled as the hydrochloride.

<span class="mw-page-title-main">Carbonyl reduction</span> Organic reduction of any carbonyl group by a reducing agent

In organic chemistry, carbonyl reduction is the conversion of any carbonyl group, usually to an alcohol. It is a common transformation that is practiced in many ways. Ketones, aldehydes, carboxylic acids, esters, amides, and acid halides - some of the most pervasive functional groups, -comprise carbonyl compounds. Carboxylic acids, esters, and acid halides can be reduced to either aldehydes or a step further to primary alcohols, depending on the strength of the reducing agent. Aldehydes and ketones can be reduced respectively to primary and secondary alcohols. In deoxygenation, the alcohol group can be further reduced and removed altogether by replacement with H.

The Pinnick oxidation is an organic reaction by which aldehydes can be oxidized into their corresponding carboxylic acids using sodium chlorite (NaClO2) under mild acidic conditions. It was originally developed by Lindgren and Nilsson. The typical reaction conditions used today were developed by G. A. Kraus. H.W. Pinnick later demonstrated that these conditions could be applied to oxidize α,β-unsaturated aldehydes. There exist many different reactions to oxidize aldehydes, but only a few are amenable to a broad range of functional groups. The Pinnick oxidation has proven to be both tolerant of sensitive functionalities and capable of reacting with sterically hindered groups. This reaction is especially useful for oxidizing α,β-unsaturated aldehydes, and another one of its advantages is its relatively low cost.

<i>N</i>-Sulfinyl imine

N-Sulfinyl imines are a class of imines bearing a sulfinyl group attached to nitrogen. These imines display useful stereoselectivity reactivity and due to the presence of the chiral electron withdrawing N-sulfinyl group. They allow 1,2-addition of organometallic reagents to imines. The N-sulfinyl group exerts powerful and predictable stereodirecting effects resulting in high levels of asymmetric induction. Racemization of the newly created carbon-nitrogen stereo center is prevented because anions are stabilized at nitrogen. The sulfinyl chiral auxiliary is readily removed by simple acid hydrolysis. The addition of organometallic reagents to N-sulfinyl imines is the most reliable and versatile method for the asymmetric synthesis of amine derivatives. These building blocks have been employed in the asymmetric synthesis of numerous biologically active compounds.

In organic chemistry, the Davis oxidation or Davis' oxaziridine oxidation refers to oxidations involving the use of the Davis reagent or other similar oxaziridine reagents. This reaction mainly refers to the generation of α-hydroxy carbonyl compounds (acyloins) from ketones or esters. The reaction is carried out in a basic environment to generate the corresponding enolate from the ketone or ester. This reaction has been shown to work for amides.

<span class="mw-page-title-main">Teruaki Mukaiyama</span> Japanese chemist (1927–2018)

Teruaki Mukaiyama was a Japanese organic chemist. One of the most prolific chemists of the 20th century in the field of organic synthesis, Mukaiyama helped establish the field of organic chemistry in Japan after World War II.

References

  1. ↑ Nomenclature of Organic Chemistry: IUPAC Recommendations and Preferred Names 2013 (Blue Book). Cambridge: The Royal Society of Chemistry. 2014. p. 375. doi:10.1039/9781849733069-00372. ISBN   978-0-85404-182-4. The name carbodiimide, for HN=C=NH, is retained but only for general nomenclature; no substitution of any kind is allowed. The systematic name, methanediimine, is the preferred IUPAC name.
  2. ↑ McGuire, Brett A.; Loomis, Ryan A.; Charness, Cameron M.; Corby, Joanna F.; Blake, Geoffrey A.; Hollis, Jan M.; Lovas, Frank J.; Jewell, Philip R.; Remijan, Anthony J. (2012-10-20). "Interstellar Carbodiimide (HNCNH): A New Astronomical Detection from the GBT Primos Survey Via Maser Emission Features". The Astrophysical Journal. 758 (2): L33. arXiv: 1209.1590 . Bibcode:2012ApJ...758L..33M. doi:10.1088/2041-8205/758/2/L33. ISSN   2041-8205. S2CID   26146516.
  3. 1 2 Andrew Williams; Ibrahim T. Ibrahim (1981). "Carbodiimide Chemistry: recent Advances". Chem. Rev. 81 (6): 589–636. doi:10.1021/cr00046a004.
  4. 1 2 T. W. Campbell; J. J. Monagle (1963). "Diphenylcarbodiimide". Org. Synth. 43: 31. doi:10.15227/orgsyn.043.0031.
  5. 1 2 Irngartinger, H.; Jäger, H.-U. (1978). "Kristall- und Molekularstrukturen von zwei Carbodiimiden: Bis(diphenylmethyl)carbodiimid und Bis(p-methoxyphenyl)-carbodiimid". Acta Crystallographica Section B: Structural Crystallography and Crystal Chemistry. 34 (11): 3262–3265. doi:10.1107/S0567740878010626.
  6. ↑ Vincent, A. T.; Wheatley, P. J. (1972). "Crystal Structure of Bis-p-nitrophenylcarbodiimide, O2N·C6H4·N:C:N·C6H4·NO2". Journal of the Chemical Society, Perkin Transactions 2 (11): 1567–1571. doi:10.1039/P29720001567.
  7. ↑ Taniguchi, Tohru; Suzuki, Takahiro; Satoh, Haruka; Shichibu, Yukatsu; Konishi, Katsuaki; Monde, Kenji (2018). "Preparation of Carbodiimides with One-Handed Axial Chirality". Journal of the American Chemical Society. 140 (46): 15577−15581. doi:10.1021/jacs.8b08969. PMID   30398863. S2CID   53231838 . Retrieved 18 August 2020.
  8. ↑ Damrauer, Robert; Lin, Hai; Damrauer, Niels H. (2014). "Computational Studies of Carbodiimide Rings". Journal of Organic Chemistry. 79 (9): 3781−3788. doi:10.1021/jo4026435. PMID   24716711 . Retrieved 18 August 2020.
  9. 1 2 3 Frederick Kurzer; K. Douraghi-Zadeh (1967). "Advances in the Chemistry of Carbodiimides". Chem. Rev. 67 (2): ee107–152. doi:10.1021/cr60246a001. PMID   4859920.
  10. ↑ Henri Ulrich (2008). Chemistry and Technology of Carbodiimides. Wiley-VCH. ISBN   978-0-470-06510-5.
  11. ↑ John C. Sheehan; Philip A. Cruickshank (1968). "1-Ethyl-3-(3-Dimethylamino)propylcarbodiimide Hydrochloride and Methiodide". Org. Synth. 48: 83. doi:10.15227/orgsyn.048.0083.
  12. ↑ Arnab K. Maity; Skye Fortier; Leonel Griego; Alejandro J. Metta-Magaña (2014). "Synthesis of a "Super Bulky" Guanidinate Possessing an Expandable Coordination Pocket". Inorg. Chem. 53 (15): 8155–8164. doi:10.1021/ic501219q. PMID   25029088.
  13. ↑ Monagle, J. J. (1962). "Carbodiimides. III. Conversion of Isocyanates to Carbodiimides. Catalyst Studies". J. Org. Chem. 27 (11): 3851–3855. doi:10.1021/jo01058a022.
  14. ↑ Li, Zhen; Mayer, Robert J.; Ofial, Armin R.; Mayr, Herbert (2020-04-27). "From Carbodiimides to Carbon Dioxide: Quantification of the Electrophilic Reactivities of Heteroallenes". Journal of the American Chemical Society. 142 (18): 8383–8402. doi:10.1021/jacs.0c01960. PMID   32338511. S2CID   216557447.
  15. ↑ Tidwell, T. T. (1990). "Oxidation of Alcohols by Activated Dimethyl Sulfoxide and Related Reactions: An Update". Synthesis. 1990 (10): 857–870. doi:10.1055/s-1990-27036.
  16. ↑ John G. Moffatt (1967). "Cholane-24-al". Org. Synth. 47: 25. doi:10.15227/orgsyn.047.0025.
  17. ↑ Hesselmans, L. C. J.; Derksen, A. J.; van den Goorbergh, J. A. M. (2006). "Polycarbodiimide crosslinkers". Progress in Organic Coatings. 55 (2): 142–148. doi:10.1016/j.porgcoat.2005.08.011. ISSN   0300-9440.
  18. ↑ Posthumus, W.; Derksen, A. J.; van den Goorbergh, J. A. M.; Hesselmans, L. C. J. (2007). "Crosslinking by polycarbodiimides". Progress in Organic Coatings. 58 (2–3): 231–236. doi:10.1016/j.porgcoat.2006.09.031. ISSN   0300-9440.
  19. ↑ Hotan Mojarradi (2010). Coupling of substances containing a primary amine to hyaluronan via carbodiimide-mediated amidation (Thesis). Uppsala Universitet. ISSN   1650-8297.
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