organic aldehyde_isothiocyanate chemistry

Organic Aldehyde/Isothiocyanate chemistry

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ContentsArticlesNucleophilic addition Tetrahedral carbonyl addition compound Nucleophilic substitution Nucleophilic acyl substitution Addition reaction Condensation reaction Substitution reaction Elimination reaction Leaving group Reductive amination Aldol condensation SN1 reaction SN2 reaction Alkylimino-de-oxo-bisubstitution SchottenBaumann reaction Mannich reaction Edman degradation Carbocation Organocatalysis Double bond Functional group Nucleophile Electrophile Sigma bond Pi bond Alkane Amine Amide Imine Schiff base Aldehyde Racemic mixture Aldimine Acid anhydride 1 3 12 15 22 23 25 27 31 32 34 39 43 46 49 50 54 55 59 63 65 74 78 82 84 86 101 109 114 117 118 125 127 128

Carboxylic acid Carbonyl Cyanide Alkoxide Acyl halide Acetyl chloride Haloalkane Hemiaminal Carboximidate Enol Hydroxylamine Oxime Nitrile Hydrogen cyanide Ethyl chloroformate Dithiocarbamate Isothiocyanate Glucosinolate Thiourea Urea Allyl isothiocyanate Methyl isothiocyanate Ethyl carbamate Carbamate Sodium diethyldithiocarbamate Thiocarbamate Pyridoxal phosphate

130 136 139 146 149 151 154 159 160 161 165 170 174 181 188 189 189 192 195 200 209 211 213 218 221 223 224

ReferencesArticle Sources and Contributors Image Sources, Licenses and Contributors 227 232

Article LicensesLicense 241

Nucleophilic addition

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Nucleophilic additionIn organic chemistry, a nucleophilic addition reaction is an addition reaction where in a chemical compound a bond is removed by the creation of two new bonds by the addition of a nucleophile.[1] Addition reactions are limited to chemical compounds that have multiple-bonded atoms: molecules with carbon hetero multiple bonds like carbonyls, imines or nitriles molecules with carbon carbon double bonds or triple bonds.

Addition to carbon hetero double bondsAddition reactions of a nucleophile to carbon hetero double bonds such as C=O or CN triple bond show a wide variety. These bonds are polar (have a large difference in electronegativity between the two atoms) consequently carbon carries a partial positive charge. This makes this atom the primary target for the nucleophile.

This type of reaction is also called a 1,2 nucleophilic addition. The stereochemistry of this type of nucleophilic attack is not an issue, when both alkyl substituents are dissimilar and there are not any other controlling issues such as chelation with a Lewis acid, the reaction product is a racemate. Addition reactions of this type are numerous. When the addition reaction is accompanied by an elimination the reaction type is nucleophilic acyl substitution or an addition-elimination reaction.

CarbonylsWith a carbonyl compound as an electrophile, the nucleophile can be: water in hydration to a geminal diol (hydrate) an alcohol in acetalisation to an acetal a hydride in reduction to an alcohol an amine with formaldehyde and a carbonyl compound in the Mannich reaction an enolate ion in an aldol reaction or BaylisHillman reaction an organometallic nucleophile in the Grignard reaction or the related Barbier reaction or a Reformatskii reaction ylides such as a Wittig reagent or the CoreyChaykovsky reagent or -silyl carbanions in the Peterson olefination a phosphonate carbanion in the HornerWadsworthEmmons reaction a pyridine zwitterion in the Hammick reaction an acetylide in the Favorskii reaction.

Nucleophilic addition

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NitrilesWith nitrile electrophiles nucleophilic addition take place by: hydrolysis of a nitrile to an amide or a carboxylic acid organozinc nucleophiles in the Blaise reaction alcohols in the Pinner reaction. the (same) nitrile -carbon in the Thorpe reaction. The intramolecular version is called the ThorpeZiegler reaction.

Addition to carbon carbon double bondsThe driving force for the addition to alkenes is the formation of a nucleophile X that forms a covalent bond with an electron-poor unsaturated system -C=C- (step 1). The negative charge on X is transferred to the carbon carbon bond.

In step 2 the negatively charged carbanion combines with (Y) that is electron-poor to form the second covalent bond. Ordinary alkenes are not susceptible to a nucleophilic attack (apolar bond). Styrene reacts in toluene with sodium to 1,3-diphenylpropane [2] through the intermediate carbanion:

Another exception to the rule is found in the Varrentrapp reaction. Fullerenes have unusual double bond reactivity and additions such has the Bingel reaction are more frequent. When X is a carbonyl group like C=O or COOR or a cyanide group (CN), the reaction type is a conjugate addition reaction. The substituent X helps to stabilize the negative charge on the carbon atom by its inductive effect. In addition when Y-Z is an active hydrogen compound the reaction is known as a Michael reaction.

Nucleophilic addition Perfluorinated alkenes (alkenes that have all hydrogens replaced by fluorine) are highly prone to nucleophilic addition, for example by fluoride ion from caesium fluoride or silver(I) fluoride to give a perfluoroalkyl anion.

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References[1] March Jerry; (1985). Advanced Organic Chemistry reactions, mechanisms and structure (3rd ed.). New York: John Wiley & Sons, inc. ISBN 0-471-85472-7 [2] Sodium-catalyzed Side Chain Aralkylation of Alkylbenzenes with Styrene Herman Pines, Dieter Wunderlich J. Am. Chem. Soc.; 1958; 80(22)60016004. doi:10.1021/ja01555a029

Tetrahedral carbonyl addition compoundTetrahedral intermediate is a reaction intermediate in which the bond arrangement around an initially double-bonded carbon atom has been transformed from trigonal to tetrahedral.[1] Tetrahedral intermediates result from nucleophilic addition to a carbonyl group. The stability of tetrahedral intermediate depends on the ability of the groups attached to the new tetrahedral carbon atom to leave with the negative charge. Tetrahedral intermediates are very significant in organic syntheses and biological systems as a key intermediate in esterification, transesterification, ester hydrolysis, formation and hydrolysis of amides and peptides, hydride reductions, and other chemical reactions.

Tetrahedral carbonyl addition compound

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HistoryOne of the earliest accounts of the tetrahedral intermediate came from Rainer Ludwig Claisen in 1887.[2] In the reaction of benzyl benzoate with sodium methoxide, and methyl benzoate with sodium benzyloxide, he observed a white precipitate which under acidic conditions yields benzyl benzoate, methyl benzoate, methanol, and benzyl alcohol. He named the likely common intermediate aditionelle Verbidung.

Victor Grignard assumed the existence of unstable tetrahedral intermediate in 1901, while investigating the reaction of esters with organomagnesium reagents.[3] The first evidence for tetrahedral intermediates in the substitution reactions of carboxylic derivatives was provided by Myron L. Bender in 1951.[4] He labeled carboxylic acid derivatives with oxygen isotope O18 and reacted these derivatives with water to make labeled carboxylic acids. At the end of the reaction he found that the remaining starting material had a decreased proportion of labeled oxygen, which is consistent with the existence of the tetrahedral intermediate.

Reaction MechanismThe nucleophilic attack on the carbonyl group proceeds via Brgi-Dunitz trajectory. The angle between the line of nucleophilic attack and the C-O bond is greater than 90. This due to a better orbital overlap between the HOMO of the nucleophile and the * LUMO of the C-O double bond.Burgi-Dunitz trajectory


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Structure of Tetrahedral IntermediatesGeneral FeaturesAlthough the tetrahedral intermediates are usually transient intermediates, many compounds of this general structures are known. The reactions of aldehydes, ketones, and their derivatives frequently have a detectable tetrahedral intermediate, while for the reactions of derivatives of carboxylic acids this is not the case. At the oxidation level of carboxylic acid derivatives, the groups such as OR, OAr, NR2, or Cl are conjugated with the carbonyl group, which means that addition to the carbonyl group is thermodynamically less favored than addition to corresponding aldehyde or ketone. Stable tetrahedral intermediates of carboxylic acid derivatives do exist and they usually possess at least one of the following four structural features: 1) polycyclic structures (e.g.tetrodotoxin)[5] 2) compounds with a strong electron-withdrawing group attached to the acyl carbon (e.g.N,N-dimethyltrifluoroacetamide)[6] 3) compounds with donor groups that are poorly conjugated with the potential carbonyl group (e.g.cyclol)[7] 4) compounds with sulfur atoms bonded to the anomeric centre (e.g.S-acylated-1,8-Naphtalenedithiol)[8] These compounds were used to study the kinetics of tetrahedral intermediate decomposition into its respective carbonyl species, and to measure the IR, UV, and NMR spectra of the tetrahedral adduct.Tetrodotoxin

X-Ray Crystal Structure DeterminationThe first x-ray crystal structures of tetrahedral intermediates were obtained from the porcine trypsin crystallized with soybean tripsin inhibitor in 1974, and the bovine trypsin crystallized with bovine pancreatic trypsin inhibitor in 1973.[9][10] In both cases the tetrahedral intermediate is stabilized in the active sites of enzymes, which have evolved to stabilize the transition state of peptide hydrolysis. Some insight into the structure of tetrahedral intermediate can be obtained from the crystal structure of N-brosylmitomycin A, crystallized in 1967.[11] The tetrahedral carbon C17 forms a 136.54pm bond with O3, which is shorter than C8-O3 bond (142.31pm). In contrast, C17-N2 bond (149.06pm) is longer than N1-C1 bond (148.75pm) and N1-C11 bond (147.85pm) due to donation of O3 lone pair into * orbital of C17-N2. This model however is forced into tetracyclic sceleton, and tetrahedral O3 is methylated which makes it a poor model overall.


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The more recent x-ray crystal structure of 1-aza-3,5,7-trimethyladamantan-2-one is a good model for cationic tetrahedral intermediate.[12] The C1-N1 bond is rather long [155.2(4)pm], and C1-O1(2) bonds are shortened [138.2(4)pm]. The protonated nitrogen atom N1 is a great amine leaving group.

In 2002 David Evans et al. observed a very stable neutral tetrahedral intermediate in the reaction of N-acylpyrroles with organometallic compounds, followed by protonation with ammounium chloride producing a carbinol.[13] The C1-N1 bond [147.84(14) pm] is longer than the usual Csp3-Npyrrole bond which range from 141.2-145.8 pm. In contrast, the C1-O1 bond [141.15(13) pm] is shorter than the average Csp3-OH bond which is about 143.2 pm. The elongated C1-N1, and shortened C1-O1 bonds are explained with an anomeric effect resulting from the interaction of the oxygen lone pairs with the *C-N orbital. Similarly, an interaction of an oxygen lone pair with *C-C orbital should be responsible for the lengthened C1-C2 bond [152.75(15) pm] compared to the average Csp2-Csp2 bonds which are 151.3 pm. Also, the C1-C11 bond [152.16(17) pm] is slightly shorter than the average Csp3-Csp3 bond which is around 153.0 pm.


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Stability of Tetrahedral IntermediatesAcetals and HemiacetalsHemiacetals and acetals are essentially tetrahedral intermediates. They form when nucleophiles add to a carbonyl group, but unlike tetrahedral intermediates they can be very stable and used as protective groups in synthetic chemistry. A very well known reaction occurs when acetaldehyde is dissolved in methanol, producing a hemiacetal. Most hemiacetals are unstable with respect to their parent aldehydes and alcohols. For example, the equilibrium constant for reaction of acetaldehyde with simple alcohols is about 0.5, where the equilibrium constant is defined as K=[hemiacetal]/[aldehyde][alcohol]. Hemiacetals of ketones (sometimes called hemiketals) are even less stable than those of aldehydes. However, cyclic hemiacetals and hemiacetals bearing electron withdrawing groups are stable. Electronwithdrawing groups attached to the carbonyl atom shift the equilibrium constant toward the hemiacetal. They increase the polarization of the carbonyl group, which already has a positively polarized carbonyl carbon, and make it even more prone to attack by a nucleophile. The chart below shows the extent of hydration of some carbonyl compounds. Hexafluoroacetone is probably the most hydrated carbonyl compound possible. Formaldehyde reacts with water so readily because its substituents are very small- a purely steric effect.[14] [15]

Cyclopropanones- three-membered ring ketones- are also hydrated to a significant extent. Since three-membered rings are very strained (bond angles forced to be 60), sp3 hybridization is more favorable than sp2 hybridization. For the sp3 hybridized hydrate the bonds have to be distorted by about 49, while for the sp2 hybridized ketone the bond

Tetrahedral carbonyl addition compound angle distortion is about 60. So the addition to the carbonyl group allows some of the strain inherent in the small ring to be released, which is why cyclopropanone and cyclobutanone are very reactive electrophiles. For larger rings, where the bond angles are not as distorted, the stability of the hemiacetals is due to entropy and the proximity of the nucleophile to the carbonyl group. Formation of an acyclic acetal involves a decrease in entropy because two molecules are consumed for every one produced. In contrast, the formation of cyclic hemiacetals involves a single molecule reacting with itself, making the reaction more favorable. Another way to understand the stability of cyclic hemiacetals is to look at the equilibrium constant as the ratio of the forward and backward reaction rate. For a cyclic hemiacetal the reaction is intramolecular so the nucleophile is always held close to the carbonyl group ready to attack, so the forward rate of reaction is much higher than the backward rate. Many biologically relevant sugars, such as glucose, are cyclic hemiacetals.

8

In the presence of acid, hemiacetals can undergo an elimination reaction, losing the oxygen atom that once belonged to the parent aldehydes carbonyl group. These oxonium ions are powerful electrophiles, and react rapidly with a second molecule of alcohol to from new, stable compounds, called acetals. The whole mechanism of acetal formation from hemiacetal is drawn bellow.


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Acetals, as already pointed out, are stable tetrahedral intermediates so they can be used as protective groups in organic synthesis. Acetals are stable under basic conditions, so they can be used to protect ketones from a base. Acetal group is hydrolyzed under acidic conditions. An example with dioxolane protecting group is given below.

Weinreb AmidesWeinreb amides are N-methoxy-Nmethyl-carboxylic acid amides.[16] Weinreb amides are reacted with organometallic compounds togive, on protonation, ketones (see Weinreb ketone synthesis). It is generally accepted that the high yields of ketones are due to the high stability of the five-membered ring- chelated intermediate. Quantum mechanical calculations have shown that thetrahedral adduct is formed easily and it is fairly stable, in agreement with the experimental results.[17] The very facile reaction of Weinreb amides with organolithium and Grignard reagents results from the chelate stabilization in the tetrahedral adduct and, more importantly, the transition state leading to the adduct. The tetrahedral adducts are shown below.


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Applications in BiomedicineDrug DesignA solvated ligand that binds the protein of interest is likely to exist as an equilibrium mixture of several conformers. Likewise the solvated protein also exists as several conformers in equilibrium. Formation of protein-ligand complex includes displacement of the solvent molecules that occupy the binding site of the ligand, to produce a solvated complex. Because this necessarily means that the interaction is entropically disfavored, highly favorable enthalpic contacts between the protein and the ligand must compensate for the entropic loss. The design of new ligands is usually based on the modification of known ligands for the target proteins. Proteases are enzymes that catalyze hydrolysis of a peptide bond. These proteins have evolved to recognize and bind the transition state of peptide hydrolysis reaction which is a tetrahedral intermediate. Therefore, the main protease inhibitors are tetrahedral intermediate mimics having an alcohol or a phosphate group. Examples are saquinavir, ritonavir, pepstatin, etc.[18]

Enzymatic ActivityStabilization of tetrahedral intermediates inside of the enzyme active site has been investigated using tetrahedral intermediate mimics. The specific binding forces involved in stabilizing the trasition state have been describe crystallographycally. In the mammalian serine proteases, trypsin and chymotrypsin, two peptide NH groups of the polypeptide backbone form the so-called oxyanion hole by donating hydrogen bonds to the negatively charged oxygen atom of the tetrahedral intermediate.[19] A simple diagram describing the interaction is shown below.


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References[1] "IUPAC Gold Book definition" (http:/ / goldbook. iupac. org/ T06289. html). . [2] Claisen, Ludwig (1887). Chem. Ber. 20: 646650. doi:10.1002/cber.188702001148. [3] Grignard, Victor (1901). Ann. Chim. Phys. 24: 433490. [4] Bender, Myron (1951). J. Am. Chem. Soc. 73: 16261629. doi:10.1021/ja01148a063. [5] Woodward, R.B.; Gougoutas J. Z. (1964). J. Am. Chem. Soc. 86: 5030. [6] Gideon, Fraenkel; Watson Debra (1975). J. Am. Chem. Soc. 97: 231232. doi:10.1021/ja00834a063. [7] Cerrini, S.; Fedeli W., Mazza F. (1971). Chem. Commun.: 16071608. doi:10.1039/C29710001607. [8] Tagaki, M.; Ishahara R., Matsudu T. (1977). Bull. Chem. Soc. Jpn. 50: 21932194. doi:10.1246/bcsj.50.2193. [9] Sweet, R.M.; Wright H.T., Clothia C.H., Blow D.M. (1974). Biochemistry 13: 42124228. doi:10.1021/bi00717a024. PMID4472048. [10] Ruhlmann, A.; Kukla D., Schwager P., Bartels K., Huber R. (1973). J. Mol. Biol. 77 (3): 417436. [11] Tulinsky, A.; Van den Hende J.H. (1967). J. Am. Chem. Soc. 89: 29052911. [12] Kirby, A. J.; Komarov I.V., Feeder N. (1998). J. Am. Chem. Soc. 120: 71017102. doi:10.1021/ja980700s. [13] Evans, D. A.; G. Borg, K. A. Scheidt (2002). Angewandte Chemie 114 (17): 332023. [14] Bell, R. P. (1966). Adv. Phys. Org. Chem. 4 (1). [15] Clayden J., Greeves N., Warren S., and Wothers P. (2001). Organic Chemistry. Oxford University Press. [16] Nahm, S.; Weinreb S. M. (1981). Tetrahedron Lett. 22: 381518. doi:10.1016/s0040-4039(01)91316-4. [17] Adler, M.; Adler S., Boche G. (2005). J. Phys. Org. Chem. 18: 193209. doi:10.1002/poc.807. [18] Babine, R. E.; Bender S. L. (1997). Chem. Rev. 97: 13591472. doi:10.1021/cr960370z. PMID11851455. [19] Bryan, P.; Pantoliano M. W., Quill S. G., Hsiao H. Y., Poulos T. (1986). Proc. Natl. Acad. Sci. USA 83: 37435.

Nucleophilic substitution

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Nucleophilic substitutionIn organic and inorganic chemistry, nucleophilic substitution is a fundamental class of reactions in which an electron nucleophile selectively bonds with or attacks the positive or partially positive charge of an atom or a group of atoms called the leaving group; the positive or partially positive atom is referred to as an electrophile.[1][2] The most general form for the reaction may be given as Nuc: + R-LG R-Nuc + LG: The electron pair (:) from the nucleophile (Nuc) attacks the substrate (R-LG) forming a new bond, while the leaving group (LG) departs with an electron pair. The principal product in this case is R-Nuc. The nucleophile may be electrically neutral or negatively charged, whereas the substrate is typically neutral or positively charged. An example of nucleophilic substitution is the hydrolysis of an alkyl bromide, R-Br, under alkaline conditions, where the attacking nucleophile is the OH and the leaving group is Br-. R-Br + OH R-OH + Br Nucleophilic substitution reactions are commonplace in organic chemistry, and they can be broadly categorised as taking place at a saturated aliphatic carbon or at (less often) a saturated aromatic or other unsaturated carbon centre.[3]

Nucleophilic substitution at saturated carbon centresSN1 and SN2 reactionsIn 1935, Edward D. Hughes and Sir Christopher Ingold studied nucleophilic substitution reactions of alkyl halides and related compounds. They proposed that there were two main mechanisms at work, both of them competing with each other. The two main mechanisms are the SN1 reaction and the SN2 reaction. S stands for chemical substitution, N stands for nucleophilic, and the number represents the kinetic order of the reaction.[4] In the SN2 reaction, the addition of the nucleophile and the elimination of leaving group take place simultaneously. SN2 occurs where the central carbon atom is easily accessible to the nucleophile. By contrast the SN1 reaction involves two steps. SN1 reactions tend to be important when the A graph showing the relative reactivities of the different alkyl halides towards SN1 central carbon atom of the substrate is and SN2 reactions (also see Table 1). surrounded by bulky groups, both because such groups interfere sterically with the SN2 reaction (discussed above) and because a highly substituted carbon forms a stable carbocation. An example of a substitution reaction taking place by a so-called borderline mechanism as originally studied by Hughes and Ingold [5] is the reaction of 1-phenylethyl chloride with sodium methoxide in methanol.

Nucleophilic substitution

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The reaction rate is found to the sum of SN1 and SN2 components with 61% (3,5 M, 70C) taking place by the latter.Nucleophilic substitution at carbon

SN1 mechanism

SN2 mechanism

Table 1. Nucleophilic substitutions on RX (an alkyl halide or equivalent) Factor Kinetics Primary alkyl Rate = k[RX] Never unless additional stabilising groups present Moderate Excellent SN1 SN2 Rate = k[RX][Nuc] Good unless a hindered nucleophile is used Moderate Never Elimination likely if heated or if strong base used For halogens, I > Br > Cl >> F Comments

Secondary alkyl Tertiary alkyl

Leaving group

Important

Important

Nucleophilicity Preferred solvent Stereochemistry Rearrangements Eliminations

Unimportant Polar protic

Important Polar aprotic

Racemisation (+ partial inversion possible) Common Common, especially with basic nucleophiles

Inversion Rare Only with heat & basic nucleophiles Side reaction Side reaction esp. if heated

Nucleophilic substitution reactionsThere are many reactions in organic chemistry that involve this type of mechanism. Common examples include Organic reductions with hydrides, for example R-X R-H using LiAlH4 (SN2) hydrolysis reactions such as R-Br + OH R-OH + Br (SN2) or R-Br + H2O R-OH + HBr (SN1) Williamson ether synthesis R-Br + OR' R-OR' + Br (SN2) The Wenker synthesis, a ring-closing reaction of aminoalcohols.

Nucleophilic substitution The Finkelstein reaction, a halide exchange reaction. Phosphorus nucleophiles appear in the Perkow reaction and the MichaelisArbuzov reaction. The Kolbe nitrile synthesis, the reaction of alkyl halides with cyanides.

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Other mechanismsBesides SN1 and SN2, other mechanisms are known, although they are less common. The SNi mechanism is observed in reactions of thionyl chloride with alcohols, and it is similar to SN1 except that the nucleophile is delivered from the same side as the leaving group. Nucleophilic substitutions can be accompanied by an allylic rearrangement as seen in reactions such as the Ferrier rearrangement. This type of mechanism is called an SN1' or SN2' reaction (depending on the kinetics). With allylic halides or sulphonates, for example, the nucleophile may attack at the unsaturated carbon in place of the carbon bearing the leaving group. This may be seen in the reaction of 1-chloro-2-butene with sodium hydroxide to give a mixture of 2-buten-1-ol and 1-buten-3-ol: The Sn1CB mechanism appears in inorganic chemistry. Competing mechanisms exist.[6][7] In organometallic chemistry the nucleophilic abstraction reaction occurs with a nucleophilic substitution mechanism. CH3CH=CH-CH2-Cl CH3CH=CH-CH2-OH + CH3CH(OH)-CH=CH2

Nucleophilic substitution at unsaturated carbon centresNucleophilic substitution via the SN1 or SN2 mechanism does not generally occur with vinyl or aryl halides or related compounds. Under certain conditions nucleophilic substitutions may occur, via other mechanisms such as those described in the nucleophilic aromatic substitution article. When the substitution occurs at the carbonyl group, the acyl group may undergo nucleophilic acyl substitution. This is the normal mode of substitution with carboxylic acid derivatives such as acyl chlorides, esters and amides.

References[1] J. March, Advanced Organic Chemistry, 4th ed., Wiley, New York, 1992. [2] R. A. Rossi, R. H. de Rossi, Aromatic Substitution by the SRN1 Mechanism, ACS Monograph Series No. 178, American Chemical Society, 1983. [ISBN 0-8412-0648-1]. [3] L. G. Wade, Organic Chemistry, 5th ed., Prentice Hall, Upper Saddle RIver, New Jersey, 2003. [4] S. R. Hartshorn, Aliphatic Nucleophilic Substitution, Cambridge University Press, London, 1973. [ISBN 0-521-09801-7] [5] 253. Reaction kinetics and the Walden inversion. Part II. Homogeneous hydrolysis, alcoholysis, and ammonolysis of -phenylethyl halidesEdward D. Hughes, Christopher K. Ingold and Alan D. Scott, J. Chem. Soc., 1937, 1201 doi:10.1039/JR9370001201 [6] N.S.Imyanitov. Electrophilic Bimolecular Substitution as an Alternative to Nucleophilic Monomolecular Substitution in Inorganic and Organic Chemistry. J. Gen. Chem. USSR (Engl. Transl.) 1990; 60 (3); 417-419. [7] Unimolecular Nucleophilic Substitution does not Exist! / N.S.Imyanitov. SciTecLibrary (http:/ / sciteclibrary. ru/ eng/ catalog/ pages/ 9330. html)

Nucleophilic acyl substitution

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Nucleophilic acyl substitutionNucleophilic acyl substitution describe a class of substitution reactions involving nucleophiles and acyl compounds. In this type of reaction, a nucleophile - such as an alcohol, amine, or enolate - displaces the leaving group of an acyl derivative - such as an acid halide, anhydride, or ester. The resulting product is a carbonyl-containing compound in which the nucleophile has taken the place of the leaving group present in the original acyl derivative. Because acyl derivatives react with a wide variety of nucleophiles, and because the product can depend on the particular type of acyl derivative and nucleophile involved, nucleophilic acyl substitution reactions can be used to synthesize a variety of different products.

Reaction mechanismCarbonyl compounds react with nucleophiles via an addition mechanism: the nucleophile attacks the carbonyl carbon, forming a tetrahedral intermediate. This reaction can be accelerated by acidic conditions, which make the carbonyl more electrophilic, or basic conditions, which provide a more anionic and therefore more reactive nucleophile. The tetrahedral intermediate itself can be an alcohol or alkoxide, depending on the pH of the reaction. The tetrahedral intermediate of an acyl compound contains a substituent attached to the central carbon that can act as a leaving group. After the tetrahedral intermediate forms, it collapses, recreating the carbonyl C=O bond and ejecting the leaving group in an elimination reaction. As a result of this two-step addition/elimination process, the nucleophile takes the place of the leaving group on the carbonyl compound by way of an intermediate state that does not contain a carbonyl. Both steps are reversible and as a result, nucleophilic acyl substitution reactions are equilibrium processes.[1] Because the equilibrium will favor the product containing the best nucleophile, the leaving group must be a comparatively poor nucleophile in order for a reaction to be practical.

Acidic conditionsUnder acidic conditions, the carbonyl group of the acyl compound 1 is protonated, which activates it towards nucleophilic attack. In the second step, the protonated carbonyl (2) is attacked by a nucleophile (HZ) to give tetrahedral intermediate 3. Proton transfer from the nucleophile (Z) to the leaving group (X) gives 4, which then collapses to eject the protonated leaving group (HX), giving protonated carbonyl compound 5. The loss of a proton gives the substitution product, 6. Because the last step involves the loss of a proton, nucleophilic acyl substitution reactions are considered catalytic in acid. Also note that under acidic conditions, a nucleophile will typically exist in its protonated form (i.e. HZ instead of Z).

Basic conditionsUnder basic conditions, a nucleophile (Nuc) attacks the carbonyl group of the acyl compound 1 to give tetrahedral alkoxide intermediate 2. The intermediate collapses and expels the leaving group (X) to give the substitution product 3. While nucleophilic acyl substitution reactions can be catalytic in base, they will not be if the leaving group is a weaker base than the nucleophile. Unlike acid-catalyzed processes, both the nucleophile and the leaving group exist as anions under basic conditions.


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This mechanism is supported by isotope labeling experiments. When ethyl propionate with an oxygen-18-labeled ethoxy group is treated with sodium hydroxide (NaOH), the oxygen-18 label is completely absent from propionic acid and is found exclusively in the ethanol.[2]

Reactivity trendsThere are five main types of acyl derivatives. Acid halides are the most reactive towards nucleophiles, followed by anhydrides, esters, and amides. Carboxylate ions are essentially unreactive towards nucleophilic substitution, since they possess no leaving group. It is interesting to note the reactivity of these five classes of compounds covers a broad range; the relative reaction rates of acid chlorides and amides differ by a factor of 1013.[3]

A major factor in determining the reactivity of acyl derivatives is leaving group ability, which is related to acidity. Weak bases are better leaving groups than strong bases; a species with a strong conjugate acid (e.g. hydrochloric acid) will be a better leaving group than a species with a weak conjugate acid (e.g. acetic acid). Thus, chloride ion is a better leaving group than acetate ion. The reactivity of acyl compounds towards nucleophiles decreases as the basicity of the leaving group increases, as the table shows.[4]Compound Name Acetyl chloride Structure Leaving Group pKa of Conjugate Acid -7

Acetic anhydride

4.76

Ethyl acetate

15.9


1738

Acetamide

Acetate anion

N/a

N/a

Another factor that plays a role in determining the reactivity of acyl compounds is resonance. Amides exhibit two main resonance forms. Both are major contributors to the overall structure, so much so that the amide bond between the carbonyl carbon and the amide nitrogen has significant double bond The two major resonance forms of an amide. character. The energy barrier for rotation about an amide bond is 75 to 85 kJ/mol (18 to 20 kcal/mol), much larger than values observed for normal single bonds. For example, the CC bond in ethane has an energy barrier of only 12 kJ/mol (3 kcal/mol).[3] Once a nucleophile attacks and a tetrahedral intermediate is formed, the energetically favorable resonance effect is lost. This helps explain why amides are one of the least reactive acyl derivatives.[4] Esters exhibit less resonance stabilization than amides, so the formation of a tetrahedral intermediate and subsequent loss of resonance is not as energetically unfavorable. Anhydrides experience even weaker resonance stabilization, since the resonance is split between two carbonyl groups, and are more reactive than esters and amides. In acid halides, there is very little resonance, so the energetic penalty for forming a tetrahedral intermediate is small. This helps explain why acid halides are the most reactive acyl derivatives.[4]

Reactions of acyl derivativesMany nucleophilic acyl substitution reactions involve converting one acyl derivative into another. In general, conversions between acyl derivatives must proceed from a relatively reactive compound to a less reactive one in order to be practical; an acid chloride can easily be converted to an ester, but converting an ester directly to an acid chloride is essentially impossible. When converting between acyl derivatives, the product will always be more stable than the starting compound. Nucleophilic acyl substitution reactions that do not involve interconversion between acyl derivatives are also possible. For example, amides and carboxylic acids react with Grignard reagents to produce ketones. An overview of the reactions that each type of acyl derivative can participate in is presented here.

Acid halidesAcid halides are the most reactive acyl derivatives, and can easily be converted into any of the others. Acid halides will react with carboxylic acids to form anhydrides. If the structure of the acid and the acid chloride are different, the product is a mixed anhydride. First, the carboxylic acid attacks the acid chloride (1) to give tetrahedral intermediate 2. The tetrahedral intermediate collapses, ejecting chloride ion as the leaving group and forming oxonium species 3. Deprotonation gives the mixed anhydride, 4, and an equivalent of HCl.


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Alcohols and amines react with acid halides to produce esters and amides, respectively, in a reaction formally known as the Schotten-Baumann reaction.[5] Acid halides hydrolyze in the presence of water to produce carboxylic acids, but this type of reaction is rarely useful, since carboxylic acids are typically used to synthesize acid halides. Most reactions with acid halides are carried out in the presence of a non-nucleophilic base, such as pyridine, to neutralize the hydrohalic acid that is formed as a byproduct. Acid halides will react with carbon nucleophiles, such as Grignards and enolates, though mixtures of products can result. While a carbon nucleophile will react with the acid halide first to produce a ketone, the ketone is also susceptible to nucleophilic attack, and can be converted to a tertiary alcohol. For example, when benzoyl chloride (1) is treated with two equivalents of a Grignard reagent, such as methyl magnesium bromide (MeMgBr), 2-phenyl-2-propanol (3) is obtained in excellent yield. Although acetophenone (2) is an intermediate in this reaction, it is impossible to isolate because it reacts with a second equivalent of MeMgBr rapidly after being formed.[6]

Unlike most other carbon nucleophiles, lithium dialkylcuprates - often called Gilman reagents - can add to acid halides just once to give ketones. The reaction between an acid halide and a Gilman reagent is not a nucleophilic acyl substitution reaction, however, and is thought to proceed via a radical pathway.[2] The Weinreb ketone synthesis can also be used to convert acid halides to ketones. In this reaction, the acid halide is first converted to an N-methoxy-N-methylamide, known as a Weinreb amide. A Weinreb amide. When a carbon nucleophile - such as a Grignard or organolithium reagent - adds to a Weinreb amide, the metal is chelated by the carbonyl and N-methoxy oxygens, preventing further nucleophilic additions.[7] In the Friedel-Crafts acylation, acid halides act as electrophiles for electrophilic aromatic substitution. A Lewis acid such as zinc chloride (ZnCl2), iron(III) chloride (FeCl3), or aluminum chloride (AlCl3) - coordinates to the halogen on the acid halide, activating the compound towards nucleophilic attack by an activated aromatic ring. For especially electron-rich aromatic rings, the reaction will proceed without a Lewis acid.[8]

AnhydridesThe chemistry of acid halides and anhydrides is similar. While anhydrides cannot be converted to acid halides, they can be converted to the remaining acyl derivatives. Anhydrides also participate in Schotten-Baumann-type reactions to furnish esters and amides from alcohols and amines, and water can hydrolyze anhydrides to their corresponding acids. As with acid halides, anhydrides can also react with carbon nucleophiles to furnish ketones and/or tertiary alcohols, and can participate in both the Friedel-Crafts acylation and the Weinreb ketone synthesis.[8] Unlike acid halides, however, anhydrides do not react with Gilman reagents.[2]

Nucleophilic acyl substitution The reactivity of anhydrides can be increased by using a catalytic amount of N,N-dimethylaminopyridine, or DMAP. Pyridine can also be used for this purpose, and acts via a similar mechanism.[5]

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First, DMAP (2) attacks the anhydride (1) to form a tetrahedral intermediate, which collapses to eliminate a carboxylate ion to give amide 3. This intermediate amide is more activated towards nucleophilic attack than the original anhydride, because dimethylaminopyridine is a better leaving group than a carboxylate. In the final set of steps, a nucleophile (Nuc) attacks 3 to give another tetrahedral intermediate. When this intermediate collapses to give the product 4, the pyridine group is eliminated and its aromaticity is restored - a powerful driving force, and the reason why the pyridine compound is a better leaving group than a carboxylate ion.

EstersEsters are less reactive than acid halides and anhydrides. As with more reactive acyl derivatives, they can react with ammonia and primary and secondary amines to give amides, though this type of reaction is not often used, since acid halides give better yields. Esters can be converted to other esters in an process known as transesterification. Transesterification can be either acid- or base-catalyzed, and involves the reaction of an ester with an alcohol. Unfortunately, because the leaving group is also an alcohol, the forward and reverse reactions will often occur at similar rates. Using a large excess of the reactant alcohol or removing the leaving group alcohol (e.g. via distillation) will drive the forward reaction towards completion, in accordance with Le Chatelier's principle.[9] Acid-catalyzed hydrolysis of esters is also an equilibrium process - essentially the reverse of the Fischer esterification reaction. Because an alcohol (which acts as the leaving group) and water (which acts as the nucleophile) have similar pKa values, the forward and reverse reactions compete with each other. As in transesterification, using a large excess of reactant (water) or removing one of the products (the alcohol) can promote the forward reaction.

Basic hydrolysis of esters, known as saponification, is not an equilibrium process; a full equivalent of base is consumed in the reaction, which produces one equivalent of alcohol and one equivalent of a carboxylate salt. The saponification of esters of fatty acids is an industrially important process, used in the production of soap.[9] Estes can undergo a variety of reactions with carbon nucleophiles. As with acid halides and anhyrides, they will react with an excess of a Grignard reagent to give tertiary alcohols. Esters also react readily with enolates. In the Claisen condensation, an enolate of one ester (1) will attack the carbonyl group of another ester (2) to give tetrahedral intermediate 3. The intermediate collapses, forcing out an alkoxide (R'O-) and producing -keto ester 4.


20

Crossed Claisen condensations, in which the enolate and nucleophile are different esters, are also possible. An intramolecular Claisen condensation is called a Dieckmann condensation or Dieckmann cyclization, since it can be used to form rings. Esters can also undergo condensations with ketone and aldehyde enolates to give -dicarbonyl compounds.[10] A specific example of this is the Baker-Venkataraman rearrangement, in which an aromatic ortho-acyloxy ketone undergoes an intramolecular nucleophilic acyl substitution and subsequent rearrangement to form an aromatic -diketone.[11] The Chan rearrangement is another example of a rearrangement resulting from an intramolecular nucleophilic acyl substitution reaction.

AmidesBecause of their low reactivity, amides do not participate in nearly as many nucleophilic substitution reactions as other acyl derivatives do. Amides are stable to water, and are roughly 100 times more stable towards hydrolysis than esters.[3] Amides can, however, be hydrolyzed to carboxylic acids in the presence of acid or base. The stability of amide bonds has biological implications, since the amino acids that make up proteins are linked with amide bonds. Amide bonds are resistant enough to hydrolysis to maintain protein shape and structure in aqueous environments, but are susceptible enough that they can be broken when necessary.[3] Primary and secondary amides do not react favorably with carbon nucleophiles. Grignard reagents and organolithiums will act as bases rather than nucleophiles, and will simply deprotonate the amide. Tertiary amides do not experience this problem, and react with carbon nucleophiles to give ketones; the amide anion (NR2-) is a very strong base and thus a very poor leaving group, so nucleophilic attack only occurs once. When reacted with carbon nucleophiles, N,N-dimethylformamide, or DMF, can be used to introduce a formyl group.[12]

Here, phenyllithium (1) attacks the carbonyl group of DMF (2), giving tetrahedral intermediate 3. Because the dimethylamide anion is a poor leaving group, the intermediate does not collapse and another nucleophilic addition does not occur. Upon acidic workup, the alkoxide is protonated to give 4, then the amine is protonated to give 5. Elimination of a neutral molecule of dimethylamine and loss of a proton give benzaldehyde, 6.

Carboxylic acidsCarboxylic acids are not especially reactive towards nucleophilic substitution, though they can be converted to other acyl derivatives. Converting a carboxylic acid to an amide is possible, but not straightforward. Instead of acting as a nucleophile, an amine will react as a base in the presence of a carboxylic acid to give the ammonium carboxylate salt. Heating the salt to above 100 C will drive off water and lead to the formation of the amide. This method of synthesizing amides is industrially important, and has laboratory applications as well.[13] In the presence of a strong acid catalyst, carboxylic acids can condense to form acid anhydrides. The condensation produces water, however, which can hydrolyze the anhydride back to the starting carboxylic acids. Thus, the formation of the anhydride via

Nucleophilic acyl substitution condensation is an equilibrium process. Under acid-catalyzed conditions, carboxylic acids will react with alcohols to form esters via the Fischer esterification reaction, which is also an equilibrium process. Alternatively, diazomethane can be used to convert an acid to an ester. While esterification reactions with diazomethane often give quantitative yields, diazomethane is only useful for forming methyl esters.[13] Thionyl chloride can be used to convert carboxylic acids to their corresponding acid chlorides. First, carboxylic acid 1 attacks thionyl chloride, and chloride ion leaves. The resulting oxonium ion 2 is activated towards nucleophilic attack and has a good leaving group, setting it apart from a normal carboxylic acid. In the next step, 2 is attacked by chloride ion to give tetrahedral intermediate 3, a chlorosulfite. The tetrahedral intermediate collapses with the loss of sulfur dioxide and chloride ion, giving protonated acid chloride 4. Chloride ion can remove the proton on the carbonyl group, giving the acid chloride 5 with a loss of HCl.

21

Phosphorus(III) chloride (PCl3) and phosphorus(IV) chloride (PCl5) will also convert carboxylic acids to acid chlorides, by a similar mechanism. One equivalent of PCl3 can react with three equivalents of acid, producing one equivalent of H3PO3, or phosphorus acid, in addition to the desired acid chloride. PCl5 reacts with carboxylic acids in a 1:1 ratio, and produces phosphorus(V) oxychloride, POCl3, as a byproduct. Carboxylic acids react with Grignard reagents and organolithiums to form ketones. The first equivalent of nucleophile acts as a base and deprotonates the acid. A second equivalent will attack the carbonyl group to create a geminal alkoxide dianion, which is protonated upon workup to give the hydrate of a ketone. Because most ketone hydrates are unstable relative to their corresponding ketones, the equilibrium between the two is shifted heavily in favor of the ketone. For example, the equilibrium constant for the formation of acetone hydrate from acetone is only 0.002.[14]

References[1] [2] [3] [4] [5] Wade 2010, pp. 996-997. McMurry, John (1996). Organic Chemistry (4th ed.). Pacifc Grove, CA: Brooks/Cole Publishing Company. pp.820821. ISBN0534238327. Carey, Francis A. (2006). Organic Chemistry (6th ed.). New York: McGraw-Hill. pp.866868. ISBN0072828374. Wade 2010, pp. 998-999. Krti, Lszl; Barbara Czak (2005). Strategic Applications of Named Reactions in Organic Synthesis. London: Elsevier Academic Press. p.398. ISBN0124297854. [6] McMurry 1996, pp. 826-827. [7] Krti and Czak 2005, p. 478. [8] Krti and Czak 2005, p. 176. [9] Wade 2010, pp. 1005-1009. [10] Carey 2006, pp. 919-924. [11] Krti and Czak 2005, p. 30. [12] Katritzky, Alan R.; Meth-Cohn, Otto; Rees, Charles W., eds. (1995). Comprehensive Organic Functional Group Transformations. 3 (1st ed.). Oxford: Pergamon Press. p.90. ISBN0080423248. [13] Wade 2010, pp. 964-965. [14] Wade 2010, p. 838.


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External links Reaction of acetic anhydride with acetone in Organic Syntheses Coll. Vol. 3, p.16; Vol. 20, p.6 Article (http:// www.orgsyn.org/orgsyn/prep.asp?prep=cv3p0016)

Addition reactionAn addition reaction, in organic chemistry, is in its simplest terms an organic reaction where two or more molecules combine to form a larger one.[1][2]Addition of chlorine to ethylene Addition reactions are limited to chemical compounds that have multiple bonds, such as molecules with carbon-carbon double bonds (alkenes), or with triple bonds (alkynes). Molecules containing carbonhetero double bonds like carbonyl (C=O) groups, or imine (C=N) groups, can undergo addition as they too have double bond character.

An addition reaction is the opposite of an elimination reaction. For instance the hydration reaction of an alkene and the dehydration of an alcohol are addition-elimination pairs. There are two main types of polar addition reactions: electrophilic addition and nucleophilic addition. Two non-polar addition reaction exists as well called free radical addition and cycloadditions. Addition reactions are also encountered in polymerizations and called addition polymerization.

Addition reactions general overview. Top to bottom: electrophilic addition to alkene, nucleophilic addition of nucleophile to carbonyl and free radical addition of halide to alkene

Addition-elimination reactionIn the related addition-elimination reaction an addition reaction is followed by an elimination reaction. In the majority of reactions it involves addition of nucleophiles to carbonyl compounds in what is called nucleophilic acyl substitution.[3] Other addition-elimination reactions are the reaction of an aliphatic amine to an imine and an aromatic amine to a Schiff base in alkylimino-de-oxo-bisubstitution. The hydrolysis of nitriles to carboxylic acids is also a form of addition-elimination.

Addition reaction

23

References[1] Morrison, R. T.; Boyd, R. N. (1983). Organic Chemistry (4th ed.). Boston: Allyn and Bacon. ISBN0-205-05838-8. [2] March, Jerry (1985), Advanced Organic Chemistry: Reactions, Mechanisms, and Structure (3rd ed.), New York: Wiley, ISBN0-471-85472-7 [3] Reaction-Map of Organic Chemistry Murov, Steven. J. Chem. Educ. 2007, 84, 1224 Abstract (http:/ / jchemed. chem. wisc. edu/ Journal/ Issues/ 2007/ Jul/ abs1224. html)

Condensation reactionA condensation reaction is a chemical reaction in which two molecules or moieties (functional groups) combine to form one single molecule, together with the loss of a small molecule.[1] When this small molecule is water, it is The condensation of two amino acids to form a peptide bond (red) with expulsion of water (blue) known as a dehydration reaction; other possible small molecules lost are hydrogen chloride, methanol, or acetic acid. The word "condensation" suggests a process in which two or more things are brought "together" (Latin "con") to form something "dense", like in condensation from gaseous to liquid state of matter; this does not imply, however, that condensation reaction products have greater density than reactants. When two separate molecules react, the condensation is termed intermolecular. A simple example is the condensation of two amino acids to form the peptide bond characteristic of proteins. This reaction example is the opposite of hydrolysis, which splits a chemical entity into two parts through the action of the polar water molecule, which itself splits into hydroxide and hydrogen ions. If the union is between atoms or groups of the same molecule, the reaction is termed intramolecular condensation, and in many cases leads to ring formation. An example is the Dieckmann condensation, in which the two ester groups of a single diester molecule react with each other to lose a small alcohol molecule and form a -ketoester product.

Dieckmann condensation reaction

Condensation reaction

24

MechanismMany condensation reactions follow a nucleophilic acyl substitution or an aldol condensation reaction mechanism. Other condensations, such as the acyloin condensation are triggered by radical or single electron transfer conditions.

Condensation reactions in polymer chemistryIn one type of polymerization reaction, a series of condensation steps take place whereby monomers or monomer chains add to each other to form longer chains. This is termed 'condensation polymerization' or 'step-growth polymerization', and occurs for example in the synthesis of polyesters or nylons. It may be either a homopolymerization of a single monomer A-B with two different end groups that condense or a copolymerization of two co-monomers A-A and B-B. Small molecules are usually liberated in these condensation steps, in contrast to polyaddition reactions with no liberation of small molecules. In general, condensation polymers form more slowly than addition polymers, often requiring heat. They are generally lower in molecular weight. Monomers are consumed early in the reaction; the terminal functional groups remain active throughout and short chains combine to form longer chains. A high conversion rate is required to achieve high molecular weights as per Carothers' equation. Bifunctional monomers lead to linear chains (and therefore thermoplastic polymers), but, when the monomer functionality exceeds two, the product is a branched chain that may yield a thermoset polymer.

ApplicationsThis type of reaction is used as a basis for the making of many important polymers, for example: nylon, polyester, and other condensation polymers and various epoxies. It is also the basis for the laboratory formation of silicates and polyphosphates. The reactions that form acid anhydrides from their constituent acids are typically condensation reactions. Many biological transformations are condensation reactions. Polypeptide synthesis, polyketide synthesis, terpene syntheses, phosphorylation, and glycosylations are a few examples of this reaction. A large number of such reactions are used in synthetic organic chemistry. Other examples include: Acyloin condensation Aldol condensation Benzoin condensation (this is not technically a condensation, but is called so for historical reasons)[1] Claisen condensation Claisen-Schmidt condensation Darzens condensation (glycidic ester condensation) Dieckmann condensation Guareschi-Thorpe condensation Knoevenagel condensation Michael condensation Pechmann condensation Rap-Stoermer condensation Self-condensation or symmetrical aldol condensation Ziegler condensation

See named reactions

Condensation reaction

25

References[1] Nic, M.; Jirat, J.; Kosata, B., eds. (2006). "Condensation Reaction" (http:/ / goldbook. iupac. org/ C01238. html). IUPAC Compendium of Chemical Terminology (Online ed.). doi:10.1351/goldbook.C01238. ISBN0-9678550-9-8. .

Substitution reactionIn a substitution reaction, a functional group in a particular chemical compound is replaced by another group.[1][2] In organic chemistry, the electrophilic and nucleophilic substitution reactions are of prime importance. Organic substitution reactions are classified in several main organic reaction types depending on whether the reagent that brings about the substitution is considered an electrophile or a nucleophile, whether a reactive intermediate involved in the reaction is a carbocation, a carbanion or a free radical or whether the substrate is aliphatic or aromatic. Detailed understanding of a reaction type helps to predict the product outcome in a reaction. It also is helpful for optimizing a reaction with regard to variables such as temperature and choice of solvent. A good example of a substitution reaction is the photochemical chlorination of methane forming methyl chloride.

chlorination of methane by chlorine

Nucleophilic substitutionNucleophilic substitution happens when the reagent is a nucleophile, which means, an atom or molecule with free electrons. A nucleophile reacts with an aliphatic substrate in a nucleophilic aliphatic substitution reaction. These substitutions can be produced by two different mechanisms: unimolecular nucleophilic substitution (SN1) and bimolecular nucleophilic substitution (SN2). The SN1 mechanism has two steps. In the first step, the leaving group departs, forming a carbocation. In the second step, the nucleophilic reagent attacks the carbocation and forms a sigma bond. This mechanism can result in either inversion or retention of configuration. An SN2 reaction has just one step. The attack of the reagent and the expulsion of the leaving group happen simultaneously. This mechanism always results in inversion of configuration. When the substrate is an aromatic compound the reaction type is nucleophilic aromatic substitution. Carboxylic acid derivatives react with nucleophiles in nucleophilic acyl substitution. This kind of reaction can be useful in preparing compouds.

Substitution reaction

26

Electrophilic substitutionElectrophiles are involved in electrophilic substitution reactions and particularly in electrophilic aromatic substitutions.

Electrophilic aromatic substitution

Electrophilic reactions to other unsaturated compounds than arenes generally lead to electrophilic addition rather than substitution.

Radical substitutionA radical substitution reaction involves radicals. An example is the Hunsdiecker reaction.

Organometallic substitutionCoupling reactions are a class of metal-catalyzed reactions involving an organometallic compound RM and an organic halide R'X that together react to a compound of the type R-R' with formation of a new carbon-carbon bond. Examples are the Heck reaction and the Ullmann reaction. Many variations exist.[3]

Substituted compoundsSubstituted compounds are chemical compounds where one or more hydrogen atoms of a core structure have been replaced with a functional group like alkyl, hydroxy, or halogen. For example benzene is a simple aromatic ring and substituted benzenes are a heterogeneous group of chemicals with a wide spectrum of uses and properties:compound general formula general structure Benzene C6H6

Toluene

C6H5-CH3

o-Xylene

C6H4(-CH3)2

Substitution reaction

27Mesitylene C6H3(-CH3)3

Phenol

C6H5-OH

Just a few substituted benzene compounds

References[1] March, Jerry (1985), Advanced Organic Chemistry: Reactions, Mechanisms, and Structure (3rd ed.), New York: Wiley, ISBN0-471-85472-7 [2] Imyanitov, Naum S. (1993). "Is This Reaction a Substitution, Oxidation-Reduction, or Transfer?". J. Chem. Educ. 70 (1): 1416. Bibcode1993JChEd..70...14I. doi:10.1021/ed070p14. [3] Elschenbroich, C.; Salzer, A. (1992). Organometallics: A Concise Introduction (2nd ed.). Weinheim: Wiley-VCH. ISBN3-527-28165-7.

Elimination reactionAn elimination reaction is a type of organic reaction in which two substituents are removed from a molecule in either a one or two-step mechanism.[2] The one-step mechanism is known as the E2 reaction, and the two-step mechanism is known as the E1 reaction. The numbers do not have to do with the number of steps in the mechanism, Elimination reaction of cyclohexanol to [1] but rather the kinetics of the reaction, bimolecular and unimolecular cyclohexene with sulfuric acid and heat respectively. In most organic elimination reactions, at least one hydrogen is lost to form the double bond: the unsaturation of the molecule increases. It is also possible that a molecule undergoes reductive elimination, by which the valence of an atom in the molecule decreases by two. An important class of elimination reactions are those involving alkyl halides, with good leaving groups, reacting with a Lewis base to form an alkene. Elimination may be considered the reverse of an addition reaction. When the substrate is asymmetric, regioselectivity is determined by Zaitsev's rule.

E2 mechanismDuring the 1920s, Sir Christopher Ingold proposed a model to explain a peculiar type of chemical reaction; the E2 mechanism. E2 stands for bimolecular elimination. The fundamental elements of the reaction are as follows: One step mechanism in which carbon-hydrogen and carbon-halogen bonds break to form a double bond. C=C Pi bond. Specificities E2 is a one-step process of elimination with a single transition state. Typically undergone by primary or secondary substituted alkyl halides The reaction rate, influenced by both the alkyl halide and the base (bimolecular), is second order. Because E2 mechanism results in formation of a pi bond, the two leaving groups (often a hydrogen and a halogen) need to be antiperiplanar. An antiperiplanar transition state has staggered conformation with lower energy than a synperiplanar transition state which is in eclipsed conformation with higher energy. The reaction mechanism involving staggered conformation is more favorable for E2 reactions (unlike E1 reactions).

Elimination reaction E2 typically uses a strong base, It needs a chemical strong enough to pull off a weakly acidic hydrogen. In order for the pi bond to be created, the hybridization of carbons need to be lowered from sp3 to sp2. The C-H bond is weakened in the rate determining step and therefore a primary deuterium isotope effect much larger than 1 (commonly 2-6) is observed. E2 is very similar to the SN2 reaction mechanism.

28

An example of this type of reaction in scheme 1 is the reaction of isobutylbromide with potassium ethoxide in ethanol. The reaction products are isobutylene, ethanol and potassium bromide.

E1 mechanismE1 is a model to explain a particular type of chemical elimination reaction. E1 stands for unimolecular elimination and has the following specificities. It is a two-step process of elimination: ionization and deprotonation. Ionization: the carbon-halogen bond breaks to give a carbocation intermediate. Deprotonation of the carbocation. E1 typically takes place with tertiary alkyl halides, but is possible with some secondary alkyl halides. The reaction rate is influenced only by the concentration of the alkyl halide because carbocation formation is the slowest step aka rate-determining step. Therefore first-order kinetics apply (unimolecular). Reaction usually occurs in complete absence of base or presence of only a weak base (acidic conditions and high temperature). E1 reactions are in competition with SN1 reactions because they share a common carbocationic intermediate. A secondary deuterium isotope effect of slightly larger than 1 (commonly 1 - 1.5) is observed. No antiperiplanar requirement. An example is the pyrolysis of a certain sulfonate ester of menthol:

Elimination reaction Only reaction product A results from antiperiplanar elimination, the presence of product B is an indication that an E1 mechanism is occurring.[3] Accompanied by carbocationic rearrangement reactions

29

An example in scheme 2 is the reaction of tert-butylbromide with potassium ethoxide in ethanol. E1 eliminations happen with highly substituted alkyl halides due to 2 main reasons. Highly substituted alkyl halides are bulky, limiting the room for the E2 one-step mechanism; therefore, the two-step E1 mechanism is favored. Highly substituted carbocations are more stable than methyl or primary substituted cations. Such stability gives time for the two-step E1 mechanism to occur. If SN1 and E1 pathways are competing, the E1 pathway can be favored by increasing the heat. Specific features : 1 . Rearrangement possible 2 . Independent of concentration and basicity of base

E2 and E1 elimination final notesThe reaction rate is influenced by halogen's reactivity; iodide and bromide being favored. Fluoride is not a good leaving group. There is a certain level of competition between elimination reaction and nucleophilic substitution. More precisely, there are competitions between E2 and SN2 and also between E1 and SN1. Substitution generally predominates and elimination occurs only during precise circumstances. Generally, elimination is favored over substitution when steric hindrance increases basicity increases temperature increases the steric bulk of the base increases (such as in Potassium tert-butoxide) the nucleophile is poor

In one study [4] the kinetic isotope effect (KIE) was determined for the gas phase reaction of several alkyl halides with the chlorate ion. In accordance with an E2 elimination the reaction with t-butyl chloride results in a KIE of 2.3. The methyl chloride reaction (only SN2 possible) on the other hand has a KIE of 0.85 consistent with a SN2 reaction because in this reaction type the C-H bonds tighten in the transition state. The KIE's for the ethyl (0.99) and isopropyl (1.72) analogues suggest competition between the two reaction modes.

Elimination reaction

30

Specific elimination reactionsThe E1cB elimination reaction is a special type of elimination reaction involving carbanions. In an addition-elimination reaction elimination takes place after an initial addition reaction and in the Ei mechanism both substituents leave simultaneously in a syn addition. In each of these elimination reactions the reactants have specific leaving groups: dehydrohalogenation, leaving group a halide. the dehydration reaction is one where the leaving group is water. the Bamford-Stevens reaction with a tosylhydrazone leaving group assisted by alkoxide the Cope reaction with an amine oxide leaving group the Hofmann elimination with quaternary amine leaving group the Chugaev reaction with a methyl xanthate leaving group the Grieco elimination with a selenoxide leaving group the Shapiro reaction with a tosylhydrazone leaving group assisted by alkyllithium Hydrazone iodination with a hydrazone leaving group assisted by iodine A Grob fragmentation with degree of unsaturation increasing in one of the leaving groups.

the KornblumDeLaMare rearrangement (elimination over a (H)C-O(OR) bond) with an alcohol leaving group forming a ketone the Takai olefination with two bulky chromium groups.

References[1] Organic Syntheses I:185 http:/ / orgsynth. org/ orgsyn/ pdfs/ CV1P0183. pdf [2] March, Jerry (1985), Advanced Organic Chemistry: Reactions, Mechanisms, and Structure (3rd ed.), New York: Wiley, ISBN0-471-85472-7 [3] Nash, J. J.; Leininger, M. A.; Keyes, K. (April 2008). "Pyrolysis of Aryl Sulfonate Esters in the Absence of Solvent: E1 or E2? A Puzzle for the Organic Laboratory". Journal of Chemical Education 85 (4): 552. Bibcode2008JChEd..85..552N. doi:10.1021/ed085p552. [4] Stephanie M. Villano, Shuji Kato, and Veronica M. Bierbaum (2006). "Deuterium Kinetic Isotope Effects in Gas-Phase SN2 and E2 Reactions: Comparison of Experiment and Theory". J. Am. Chem. Soc. 128 (3): 736737. doi:10.1021/ja057491d. PMID16417360.

Leaving group

31

Leaving groupIn chemistry, a leaving group is a molecular fragment that departs with a pair of electrons in heterolytic bond cleavage. Leaving groups can be anions or neutral molecules. Common anionic leaving groups are halides such as Cl, Br, and I, and sulfonate esters, such as para-toluenesulfonate ("tosylate", TsO). Common neutral molecule leaving groups are water (H2O), and ammonia.

In this SN2 reaction, bromide (Br) acts as the leaving group and hydroxide (OH) as the nucleophile.

The ability of a leaving group to depart is correlated with the pKa of the conjugate acid, with lower pKa being associated with better leaving group ability. The correlation is not perfect because leaving group ability is a kinetic phenomenon, relating to a reaction's rate, whereas pKa is a thermodynamic phenomenon, describing the position of an equilibrium. Nevertheless, it is a general rule that more highly stabilized anions act as better leaving groups. Consistent with this rule, strong bases such as alkoxide (RO), hydroxide (HO), and amide (R2N) are poor leaving groups.Leaving groups ordered approximately in decreasing ability to leave *R-N2+ R-OR'2+ R-OSO2C4F9 R-OSO2CF3 R-OSO2F R-OTs, R-OMs, etc. R-I R-Br R-OH2+ R-Cl R-OHR'+ diazonium salts oxonium ions nonaflates triflates fluorosulfonates tosylates, mesylates, and similar iodides bromides (Conjugate acid of an alcohol) chlorides, and acyl chloride when attached to carbonyl carbon Conjugate acid of an ether [1]

R-ONO2, R-OPO(OH)2 nitrates, phosphates, and other inorganic esters R-SR'2+ R-NR'3+ R-F R-OCOR R-NH3+ tetraalkylammonium salts fluorides esters, and acid anhydrides when attached to carbonyl carbon ammonium salts

Leaving group

32R-OAr R-OH R-OR phenoxides alcohols, and carboxylic acids when attached to carbonyl carbon ethers, and esters when attached to carbonyl carbon

It is uncommon for groups such as H- (hydrides), R3C- (alkyl anions, R=alkyl or H), or R2N- (amides, R=alkyl or H) to depart with a pair of electrons because of the instability of these bases. However, the requirement for a good leaving group is relaxed in the case of E1cb mechanisms, such as the elimination step in the addition-elimination mechanism of nucleophilic acyl substitutions. Here, alkoxides and even amides can act as leaving groups due to the entropic favorability of having one molecule split into two.

References[1] Smith, March. Advanced Organic Chemistry 6th ed. (501-502)

Reductive aminationReductive amination (also known as reductive alkylation) is a form of amination that involves the conversion of a carbonyl group to an amine via an intermediate imine. The carbonyl group is most commonly a ketone or an aldehyde.

Reaction processIn this organic reaction, the amine first reacts with the carbonyl group to form a hemiaminal species, which subsequently loses one molecule of water in a reversible manner by alkylimino-de-oxo-bisubstitution, to form the imine. The equilibrium between aldehyde/ketone and imine can be shifted toward imine formation by removal of the formed water through physical or chemical means. This intermediate imine can then be isolated and reduced with a suitable reducing agent (e.g., sodium borohydride). This is indirect reductive amination. However, it is also possible to carry out the same reaction simultaneously, with the imine formation and reduction occurring concurrently. This is known as direct reductive amination, and is carried out with reducing agents that are more reactive toward protonated imines than ketones, and that are stable under moderately acidic conditions. These include sodium cyanoborohydride (NaBH3CN) and sodium triacetoxyborohydride (NaBH(OCOCH3)3).[1] This reaction has in recent years been performed in an aqueous environment casting doubt on the necessity of forming the imine.[2] This is because the loss of the water molecule is thermodynamically disfavoured by the presence of a large amount of water in its environment, as seen in the work of Turner et al.[3] Therefore, this suggests that in some cases the reaction proceeds via direct reduction of the hemiaminal species.[4]

Reductive amination

33

Variations and related reactionsThis reaction is related to the Eschweiler-Clarke reaction in which amines are methylated to tertiary amines, the Leuckart-Wallach reaction with formic acid and to other amine alkylation methods as the Mannich reaction and the Petasis reaction. A classic named reaction is the Mignonac Reaction (1921) [5] involving reaction of a ketone with ammonia over a nickel catalyst for example in a synthesis of 1-phenylethylamine starting from acetophenone:[6]

In industry, tertiary amines such as triethylamine and diisopropylethylamine are formed directly from ketones with a gaseous mixture of ammonia and hydrogen and a suitable catalyst.

BiochemistryA step in the biosynthesis of many -amino acids is the reductive amination of an -ketoacid, usually by a transaminase enzyme. The process is catalyzed by pyridoxamine phosphate, which is converted into pyridoxal phosphate after the reaction. The initial step entails formation of an imine, but the hydride equivalents are supplied by a reduced pyridine to give an aldimine, which hydrolyzes to the amine.[7] The sequence from keto-acid to amino acid can be summarized as follows: HO2CC(O)R HO2CC(=NCH2-X)R HO2CCH(N=CH-X)R HO2CCH(NH2)R.

References[1] Ellen W. Baxter and Allen B. Reitz, Reductive Aminations of Carbonyl Compounds with Borohydride and Borane Reducing Agents, Organic Reactions, 1, 59, 2002 ( Review (http:/ / www. mrw2. interscience. wiley. com/ ordb/ articles/ or059. 01/ abstract-fs. html)) [2] Shinya Sato, Takeshi Sakamoto, Etsuko Miyazawa and Yasuo Kikugawa, One-Pot Reductive Amination of Aldehydes and Ketones with -Picoline Borane in Methanol, in Water, and in Neat Conditions, Tetrahedron, 7899-7906, 60, 2004, doi:10.1016/j.tet.2004.06.045 [3] Colin J. Dunsmore, Reuben Carr, Toni Fleming and Nicholas J. Turner, A Chemo-Enzymatic Route to Enantiomerically Pure Cyclic Tertiary Amines, J Am Chem Soc, 2224-2225, 128(7), 2006 [4] V. A. Tarasevich and N. G. Kozloz, Reductive Amination of Oxygen-Containing Organic Compounds, Russian Chemical Reviews, 68(1), 55-72, 1999 [5] Nouvelle mthodegnrale de prparation des amines partir des aldhydes ou des ctones. (http:/ / gallica. bnf. fr/ ark:/ 12148/ bpt6k3125x/ f37. chemindefer) M. Georges Mignonac, Compt. rend., 172, 223 (1921). [6] John C. Robinson, Jr. and H. R. Snyder (1955), "-Phenylethylamine" (http:/ / www. orgsyn. org/ orgsyn/ orgsyn/ prepContent. asp?prep=cv3p0717), Org. Synth., ; Coll. Vol. 3: 717 [7] Nelson, D. L.; Cox, M. M. "Lehninger, Principles of Biochemistry" 3rd Ed. Worth Publishing: New York, 2000. ISBN 1-57259-153-6.

External links Current methods for reductive amination (http://www.organic-chemistry.org/synthesis/C1N/amines/ reductiveamination.shtm) Industrial Reductive amination at BASF (http://www2.basf.de/en/intermed/nbd/technology/amination. htm?id=V00-mR-a29Q3ebw20L7)

Aldol condensation

34

Aldol condensationAn aldol condensation is an organic reaction in which an enol or an enolate ion reacts with a carbonyl compound to form a -hydroxyaldehyde or -hydroxyketone, followed by a dehydration to give a conjugated enone.

Aldol condensations are important in organic synthesis, providing a good way to form carboncarbon bonds. The Robinson annulation reaction sequence features an aldol condensation; the Wieland-Miescher ketone product is an important starting material for many organic syntheses. Aldol condensations are also commonly discussed in university level organic chemistry classes as a good bond-forming reaction that demonstrates important reaction mechanisms.[1][2][3] In its usual form, it involves the nucleophilic addition of a ketone enolate to an aldehyde to form a -hydroxy ketone, or "aldol" (aldehyde + alcohol), a structural unit found in many naturally occurring molecules and pharmaceuticals.[4][5][6]

The name aldol condensation is also commonly used, especially in biochemistry, to refer to just the first (addition) stage of the processthe aldol reaction itselfas catalyzed by aldolases. However, the aldol reaction is not formally a condensation reaction because it does not involve the loss of a small molecule. The reactions between a ketone and a carbonyl compound lacking an alpha-Hydrogen(Cross Aldol condensation) is called Claisen-Schmidt condensation. These reactions are named after two of its pioneering investigators Rainer Ludwig Claisen and J. G. Schmidt, who independently published on this topic in 1880 and 1881.[7][8][9] An example is the synthesis of dibenzylideneacetone.

Aldol condensation

35

MechanismThe first part of this reaction is an aldol reaction, the second part a dehydrationan elimination reaction(Involves removal of a water molecule or an alcohol molecule). Dehydration may be accompanied by decarboxylation when an activated carboxyl group is present. The aldol addition product can be dehydrated via two mechanisms; a strong base like potassium t-butoxide, potassium hydroxide or sodium hydride in an enolate mechanism,[10] or in an acid-catalyzed enol mechanism.

:

Aldol condensation

36

Condensation typesIt is important to distinguish the aldol condensation from other addition reactions to carbonyl compounds. When the base is an amine and the active hydrogen compound is sufficiently activated the reaction is called a Knoevenagel condensation. In a Perkin reaction the aldehyde is aromatic and the enolate generated from an anhydride. A Claisen condensation involves two ester compounds. A Dieckmann condensation involves two ester groups in the same molecule and yields a cyclic molecule A Henry reaction involves an aldehyde and an aliphatic nitro compound. A Robinson annulation involves a ,-unsaturated ketone and a carbonyl group, which first engage in a Michael reaction prior to the aldol condensation. In the Guerbet reaction, an aldehyde, formed in situ from an alcohol, self-condenses to the dimerized alcohol. In the Japp-Maitland condensation water is removed not by an elimination reaction but by a nucleophilic displacement

Aldox processIn industry the Aldox process developed by Royal Dutch Shell and Exxon, converts propylene and syngas directly to 2-Ethylhexanol via hydroformylation to butyraldehyde, aldol condensation to 2-ethylhexenal and finally hydrogenation.[11]

In one study crotonaldehyde is directly converted to 2-ethylhexanal in a palladium / Amberlyst / supercritical carbon dioxide system [12]:

ScopeEthyl 2-methylacetoacetate and campholenic aldehyde react in an Aldol condensation.[13] The synthetic procedure [14] is typical for this type of reactions. In the process, in addition to water, an equivalent of ethanol and carbon dioxide are lost in decarboxylation.

Ethyl glyoxylate 2 and diethyl 2-methylglutaconate 1 react to isoprenetricarboxylic acid 3 (isoprene skeleton) with sodium ethoxide. This reaction product is very unstable with initial loss of carbon dioxide and followed by many secondary reactions. This is believed to be due to steric strain resulting from the methyl group and the carboxylic

Aldol condensation group in the cis-dienoid structure.[15]

37

Occasionally an aldol condensation is buried in a multistep reaction or in catalytic cycle such as the one sketched below:[16]

In this reaction an alkynal 1 is converted into a cycloalkene 7 with a ruthenium catalyst and the actual condensation takes place with intermediate 3 through 5. Support for the reaction mechanism is based on isotope labeling.[17] The reaction between menthone and anisaldehyde is complicated due to steric shielding of the ketone group. The solution is use of a strong base such as potassium hydroxide and a very polar solvent such as DMSO in the reaction below [18]:

Aldol condensation

38

Due to epimerization through a common enolate ion (intermediate A) the reaction product has (R,R) cis configuration and not (R,S) trans as in the starting material. Because it is only the cis isomer that precipitates from solution this product is formed exclusively.

References[1] Wade, L. G. (2005). Organic Chemistry (6th ed.). Upper Saddle River, NJ: Prentice Hall. pp.10561066. ISBN0-13-236731-9. [2] Smith, M. B.; March, J. (2001). Advanced Organic Chemistry (5th ed.). New York: Wiley Interscience. pp.12181223. ISBN0-471-58589-0. [3] Mahrwald, R. (2004). Modern Aldol Reactions. 1, 2. Weinheim, Germany: Wiley-VCH. pp.12181223. ISBN3-527-30714-1. [4] Heathcock, C. H. (1991). Additions to C-X -Bonds, Part 2. Comprehensive Organic Synthesis. Selectivity, Strategy and Efficiency in Modern Organic Chemistry. 2. Oxford: Pergamon. pp.133179. ISBN0-08-040593-2. [5] Mukaiyama T. (1982). "The Directed Aldol Reaction". Organic Reactions 28: 203331. doi:10.1002/0471264180.or028.03. [6] Paterson, I. (1988). "New Asymmetric Aldol Methodology Using Boron Enolates". Chemistry and Industry (London: Paterson Group) 12: 390394. [7] Claisen, L.; Claparde, A. (1881). "Condensationen von Ketonen mit Aldehyden" (http:/ / gallica. bnf. fr/ ark:/ 12148/ bpt6k906939/ f871. chemindefer). Berichte der Deutschen Chemischen Gesellschaft 14 (1): 24602468. doi:10.1002/cber.188101402192. . [8] Schmidt, J. G. (1881). "Ueber die Einwirkung von Aceton auf Furfurol und auf Bittermandell in Gegenwart von Alkalilauge" (http:/ / gallica. bnf. fr/ ark:/ 12148/ bpt6k90692z/ f1461. chemindefer). Berichte der Deutschen Chemischen Gesellschaft 14 (1): 14591461. doi:10.1002/cber.188101401306. . [9] March, J. (1985). Advanced Organic Chemistry: Reactions, Mechanisms and Structure (3rd ed.). Wiley Interscience. ISBN0-471-85472-7. [10] Nielsen, A. T.; Houlihan., W. J. (1968). "The Aldol Condensation". Organic Reactions 16: 1438. doi:10.1002/0471264180.or016.01. [11] For example BG 881979 (http:/ / worldwide. espacenet. com/ textdoc?DB=EPODOC& IDX=BG881979) [12] Seki, T.; Grunwaldt, J.-D.; Baiker, A. (2007). "Continuous catalytic "one-pot" multi-step synthesis of 2-ethylhexanal from crotonaldehyde". Chemical Communications 2007 (34): 35623564. doi:10.1039/b710129e. [13] Bada, C.; Castro, J. M.; Linares-Palomino, P. J.; Salido, S.; Altarejos, J.; Nogueras, M.; Snchez, A. (2004). "(E)-6-(2,2,3-Trimethyl-cyclopent-3-enyl)-hex-4-en-3-one" (http:/ / www. mdpi. com/ 1422-8599/ 2004/ 1/ M388/ pdf) (pdf). Molbank 2004 (1): M388. doi:10.3390/M388. . [14] Ethyl 2-methylacetoacetate (2) is added to a stirred solution of sodium hydride in dioxane. Then campholenic aldehyde (1) is added and the mixture refluxed for 15 h. Then 2N hydrochloric acid is added and the mixture extracted with diethyl ether. The combined organic layers are washed with 2N hydrochloric acid, saturated sodium bicarbonate and brine. The organic phase is dried over anhydrous sodium sulfate and the solvent evaporated under reduced pressure to yield a residue that was purified by vacuum distillation to give 3 (58%). [15] Goren, M. B.; Sokoloski, E. A.; Fales, H. M. (2005). "2-Methyl-(1Z,3E)-butadiene-1,3,4-tricarboxylic Acid, "Isoprenetricarboxylic Acid"". Journal of Organic Chemistry 70 (18): 74297431. doi:10.1021/jo0507892. PMID16122270.

Aldol condensation[16] Varela, J. A.; Gonzalez-Rodriguez, C.; Rubin, S. G.; Castedo, L.; Saa, C. (2006). "Ru-Catalyzed Cyclization of Terminal Alkynals to Cycloalkenes". Journal of the American Chemical Society 128 (30): 95769577. doi:10.1021/ja0610434. PMID16866480. [17] The ruthenium catalyst, [CpRu(CH3CN)3]PF6, has a cyclopentadienyl ligand, three acetonitrile ligands and a phosphorus hexafluoride counterion; the acidic proton in the solvent (acetic acid) is replaced by deuterium for isotopic labeling. Reaction conditions: 90C, 24 hrs. 80% chemical yield. The first step is formation of the Transition metal carbene complex 2. Acetic acid adds to this intermediate in a nucleophilic addition to form enolate 3 followed by aldol condensation to 5 at which stage a molecule of carbon monoxide is lost to 6. The final step is reductive elimination to form the cycloalkene. [18] Vashchenko, V.; Kutulya, L.; Krivoshey, A. (2007). "Simple and Effective Protocol for Claisen-Schmidt Condensation of Hindered Cyclic Ketones with Aromatic Aldehydes". Synthesis 2007 (14): 21252134. doi:10.1055/s-2007-983746.

39

SN1 reactionThe SN1 reaction is a substitution reaction in organic chemistry. "SN" stands for nucleophilic substitution and the "1" represents the fact that the rate-determining step is unimolecular.[1][2] Thus, the rate equation is often shown as having first-order dependence on electrophile and zero-order dependence on nucleophile. This relationship holds for situations where the amount of nucleophile is much greater than that of the carbocation intermediate. Instead, the rate equation may be more accurately described using steady-state kinetics. The reaction involves a carbocation intermediate and is commonly seen in reactions of secondary or tertiary alkyl halides under strongly basic conditions or, under strongly acidic conditions, with secondary or tertiary alcohols. With primary alkyl halides, the alternative SN2 reaction occurs. In inorganic chemistry, the SN1 reaction is often known as the dissociative mechanism. This dissociation pathway is well-described by the cis effect. A reaction mechanism was first proposed by Christopher Ingold et al. in 1940.[3] This reaction does not take account much on the strength of the nucleophile unlike the SN2 mechanism.

MechanismAn example of a reaction taking place with an SN1 reaction mechanism is the hydrolysis of tert-butyl bromide with water forming tert-butanol:

This SN1 reaction takes place in three steps: Formation of a tert-butyl carbocation by separation of a leaving group (a bromide anion) from the carbon atom: this step is slow and reversible.[4]

Nucleophilic attack: the carbocation reacts with the nucleophile. If the nucleophile is a neutral molecule (i.e. a solvent) a third step is required to complete the reaction. When the solvent is water, the intermediate is an oxonium ion. This reaction step is fast.

SN1 reaction

40

Deprotonation: Removal of a proton on the protonated nucleophile by water acting as a base forming the alcohol and a hydronium ion. This reaction step is fast.

Scope of the reactionThe SN1 mechanism tends to dominate when the central carbon atom is surrounded by bulky groups because such groups sterically hinder the SN2 reaction. Additionally, bulky substituents on the central carbon increase the rate of carbocation formation because of the relief of steric strain that occurs. The resultant carbocation is also stabilized by both inductive stabilization and hyperconjugation from attached alkyl groups. The Hammond-Leffler postulate suggests that this too will increase the rate of carbocation formation. The SN1 mechanism therefore dominates in reactions at tertiary alkyl centers and is further observed at secondary alkyl centers in the presence of weak nucleophiles. An example of a reaction proceeding in a SN1 fashion is the synthesis of 2,5-dichloro-2,5-dimethylhexane from the corresponding diol with concentrated hydrochloric acid [5]:

As the alpha and beta substitutions increase with respect to leaving groups the reaction is diverted from SN2 to SN1.

StereochemistryThe carbocation intermediate formed in the reaction's rate limiting step is an sp2 hybridized carbon with trigonal planar molecular geometry. This allows two different avenues for the nucleophilic attack, one on either side of the planar molecule. If neither avenue is preferentially favored, these two avenues occur equally, yielding a racemic mix of enantiomers if the reaction takes place at a stereocenter.[6] This is illustrated below in the SN1 reaction of S-3-chloro-3-methylhexane with an iodide ion, which yields a racemic mixture of 3-iodo-3-methylhexane:

SN1 reaction

41

However, an excess of one stereoisomer can be observed, as the leaving group can remain in proximity to the carbocation intermediate for a short time and block nucleophilic attack. This stands in contrast to the SN2 mechanism, which is a stereospecific mechanism where stereochemistry is always inverted as the nucleophile comes in from the rear side of the leaving group.

Side reactionsTwo common side reactions are elimination reactions and carbocation rearrangement. If the reaction is performed under warm or hot conditions (which favor an increase in entropy), E1 elimination is likely to predominate, leading to formation of an alkene. At lower temperatures, SN1 and E1 reactions are competitive reactions and it becomes difficult to favor one over the other. Even if the reaction is performed cold, some alkene may be formed. If an attempt is made to perform an SN1 reaction using a strongly basic nucleophile such as hydroxide or methoxide ion, the alkene will again be formed, this time via an E2 elimination. This will be especially true if the reaction is heated. Finally, if the carbocation intermediate can rearrange to a more stable carbocation, it will give a product derived from the more stable carbocation rather than the simple substitution product.

Solvent effectsSince the SN1 reaction involves formation of an unstable carbocation intermediate in the rate-determining step, anything that can facilitate this will speed up the reaction. The normal solvents of choice are both polar (to stabilize ionic intermediates in general) and protic (to solvate the leaving group in particular). Typical polar protic solvents include water and alcohols, which will also act as nucleophiles and the process is known as solvolysis. The Y scale correlates solvolysis reaction rates of any solvent (k) with that of a standard solvent (80% v/v ethanol/water) (k0) through

with m a reactant constant (m = 1 for tert-butyl chloride) and Y a solvent parameter.[7] For example 100% ethanol gives Y = 2.3, 50% ethanol in water Y = +1.65 and 15% concentration Y = +3.2.[8]

SN1 reaction

42

References[1] L. G. Wade, Jr., Organic Chemistry, 6th ed., Pearson/Prentice Hall, Upper Saddle River, New Jersey, USA, 2005 [2] March, J. (1992). Advanced Organic Chemistry (4th ed.). New York: Wiley. ISBN0-471-60180-2. [3] Leslie C. Bateman, Mervyn G. Church, Edward D. Hughes, Christopher K. Ingold and Nazeer Ahmed Taher (1940). "188. Mechanism of substitution at a saturated carbon atom. Part XXIII. A kinetic demonstration of the unimolecular solvolysis of alkyl halides. (Section E) a general discussion". Journal of the Chemical Society (Resumed): 979. doi:10.1039/JR9400000979. [4] Peters, K. S. (2007). "Nature of Dynamic Processes Associated with the SN1 Reaction Mechanism". Chem. Rev. 107 (3): 859873. doi:10.1021/cr068021k. PMID17319730. [5] Synthesis of 2,5-Dichloro-2,5-dimethylhexane by an SN1 Reaction Carl E. Wagner and Pamela A. Marshall , J. Chem. Educ., 2010, 87 (1), pp 8183 doi:10.1021/ed8000057 [6] Sorrell, Thomas N. "Organic Chemistry, 2nd Edition" University Science Books, 2006 [7] Ernest Grunwald and S. Winstein (1948). "The Correlation of Solvolysis Rates". J. Am. Chem. Soc. 70 (2): 846. doi:10.1021/ja01182a117. [8] Arnold H. Fainberg and S. Winstein (1956). "Correlation of Solvolysis Rates. III.1 t-Butyl Chloride in a Wide Range of Solvent Mixtures". J. Am. Chem. Soc. 78 (12): 2770. doi:10.1021/ja01593a033.

Further reading Electrophilic Bimolecular Substitution as an Alternative to Nucleophilic Monomolecular Substitution in Inorganic and Organic Chemistry / N.S.Imyanitov. J. Gen. Chem. USSR (Engl. Transl.) 1990; 60 (3); 417-419. Unimolecular Nucleophilic Substitution does not Exist! / N.S.Imyanitov. SciTecLibrary (http://sciteclibrary.ru/ eng/catalog/pages/9330.html)

External links Diagrams (http://www.chemhelper.com/sn1.html): Frostburg State University Exercise (http://www.usm.maine.edu/~newton/Chy251_253/Lectures/Sn1/Sn1FS.html): the University of Maine Study Organic Chemistry (http://www.study-organic-chemistry.com), Resources for Success in Organic Chemistry

organic aldehyde_isothiocyanate chemistry

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