For the hydride reductions shown in the first three equations below, this is the case. However, not all compounds of this kind give clean 1,2-reduction. Lithium aluminum hydride often reacts further with allylic alcohols, reducing the carbon-carbon double bond as well.
It must therefore be used with care. Sodium borohydride may also give conjugate addition products in some cases. Fortunately, this can be prevented by adding cerium trichloride CeCl 3 to the reaction mixture. If the 1,4-reduction product is desired it is best obtained by using a dissolving metal reduction.
The remaining five equations displayed here describe the use of various organometallic reagents. Alkyl lithium compounds usually give 1,2-addition products, as shown in equation 4. Grignard reagents, on the other hand, may add in both a 1,2- and 1,4-manner, depending on the substitution at the electrophilic sites.
Unsaturated aldehydes usually give 1,2-addition, as in equation 5. An equivalent ketone having a large carbonyl substituent, as in equation 6, gives 1,4-addition, and if the isopropyl group is replaced by a smaller methyl group a nearly mixture of 1,2- and 1,4-addition products is obtained.
Grignard reactions may be shifted to a 1,4-addition mode by adding copper salts, but a better strategy is to use a Gilman reagent , as shown in the last two equations. The metal enolate that results from this conjugate addition may be quenched by hydrolysis, as in equation 7, trapped as a silyl enol ether , as in equation 8, or alkylated by a suitable alkyl halide. The increased acidity and reactivity of C-H bonds alpha to a carbonyl group has been described.
This characteristic is critical to useful synthetic reactions such as the aldol and Claisen condensations, as well as enolate alkylation. A vinylagous or doubly vinylagous relationship results in a similar activation of a more remote carbon, which is illustrated by the resonance structures in the green shaded box below.
Here the negative charge on the conjugate base is delocalized at three atoms, the oxygen and the alpha and gamma carbons. Some reactions of such extended enolate anions with electrophilic reagents are shown below the resonance diagram. Examples 1 and 2 correspond to aldol and Claisen condensations respectively. The new carbon bonds are colored magenta. In the first case the dienolate anion can react with an electrophile at either the alpha or gamma carbons.
The reversibility of the aldol reaction favors formation of the most stable product, which is the extended conjugated dienal formed by condensation at the gamma location. The second condensation is also reversible and takes place at the end epsilon carbon.
The third example is an alkylation and is irreversible. Reaction is fastest at the alpha carbon atom of the dienolate anion, and once an alkyl group is bonded there it will not change location. Eight reactions using chemical reactions similar to those described above and in the dissolving metals reduction section are displayed here. Answers will be given by clicking the appropriate button.
Differences in the carbonyl stretching frequencies of carboxylic acid derivatives provide a useful diagnostic tool for distinguishing these compounds. Acetone is a useful reference compound strong absorption at cm -1 , since the methyl group substituents exert a minor inductive effect and do not carry a non-bonding electron pair.
Oxygen also exerts a strong inductive effect, but the resonance effect is also strong and almost balances the former. Note that both oxygen and nitrogen substituents activate benzene toward electrophilic substitution reactions.
We have noted that nucleophilic substitution reactions of carboxylic acid derivatives proceed by an addition-elimination mechanism. Of course, these acylation reactions are also are influenced by and reflect the reactivity of the nucleophilic reactant. A useful way of evaluating the relative reactivities of anionic nucleophiles is based on the pK a 's of their corresponding conjugate acids.
Weak acids have strong reactive conjugate bases, and this often but not always parallels nucleophilicity. As expected, negatively charged nucleophiles are generally much more reactive than the corresponding neutral compounds. The interplay of these two reactivity profiles nucleophile and acyl derivative , in the context of the addition-elimination mechanism, provides a useful overview of this important reaction class.
Four examples are illustrative:. Both steps in this transformation appear to be fast, and the ester and chloride anion products are both stable. The first step is probably slower than the second, and the products are an ester together with solvated HCl. R''NH 2 and a moderate electrophile e. In this case the products an amide and an alcohol are both stable, and the first step is probably rate determining. The reverse acylation in this case is so slow as to be nonexistent, presumably due to a high activation barrier to the first addition step.
Despite this thermodynamic advantage, hydrolysis reactions of amides are usually very slow. Unreactive combinations, such as that in case iv , can often be induced to react by heating or by introduction of acid or base catalysts. Heating provides energy to overcome a prohibitive activation energy barrier.
Acid and base catalysts serve to generate more reactive species electrophiles or nucleophiles that facilitate the first step. In case iv these catalysts might function as follows:. Acid Catalysis Base Catalysis.
Note also that acidic or basic reaction conditions serve to stabilize one or the other of the hydrolysis products as a stabilized ion ammonium or carboxylate. Additional Hydroxyl Substitution Methods. These reagents are generally preferred over the use of concentrated HX due to the harsh acidity of these hydrohalic acids and the carbocation rearrangements associated with their use. Of course, it is possible to avoid such problems by first preparing a mesylate or tosylate derivative, followed by nucleophilic substitution of the sulfonate ester by the appropriate halide anion.
In this two-step approach, a clean configurational inversion occurs in the first S N 2 reaction; however, the resulting alkyl halide may then undergo repeated S N 2 halogen exchange reactions, thus destroying any stereoisomeric identity held by the initial carbinol carbon. For these and other reasons, alternative mild and selective methods for transforming such alcohols by nucleophilic substitution of the hydroxyl group have been devised.
Despite their general usefulness, phosphorous tribromide and thionyl chloride have shortcomings. By clicking on this equation , an abbreviated mechanism for the reaction will be displayed. The initially formed trialkylphosphite ester may be isolated if the HBr byproduct is scavenged by base.
In the presence of HBr a series of acid-base and S N 2 reactions take place, along with the transient formation of carbocation intermediates.
Rearrangement pink arrows of the carbocations leads to isomeric products. In the presence of a base such as pyridine, the intermediate chlorosulfite ester reacts to form an "pyridinium" salt, which undergoes a relatively clean S N 2 reaction to the inverted chloride. In ether and similar solvents the chlorosulfite reacts with retention of configuration, presumably by way of a tight or intimate ion pair. This is classified as an S N i reaction nucleophilic substitution internal.
The carbocation partner in the ion pair may also rearrange. These reactions are illustrated by the following equations. An alternative explanation for the retention of configuration, involving an initial solvent molecule displacement of the chlorosulfite group as SO 2 and chloride anion , followed by chloride ion displacement of the solvent moiety, has been suggested. In this case, two inversions lead to retention. Another characteristic of thionyl chloride reactions is their tendency to give allylic rearrangement products with allylic alcohols.
This fact is demonstrated by the following equations. Reactions of this kind have been classified as S N i' , where the prime mark indicates an allylic character to the internal substitution. They may also be considered retro-ene reactions , a special class of pericyclic reactions. A similar substitutive rearrangement also occurs with propargyl alcohols, as shown by clicking on the equations. The ability of phosphorous to assume many different valencies or oxidation states was noted elsewhere.
The nucleophilicity of trialkyl phosphines allows them to bond readily to electrophiles, and the resulting phosphonium ions may then bond reversibly to other nucleophiles, especially oxygen nucleophiles. The use of phosphorous ylides in the Wittig reaction is an example of this reactivity.
The reaction of triphenylphosphine with halogens further illustrates this hypervalency. As shown in the following diagram, triphenylphosphine yellow box on the left reacts to form a pentavalent dihalide, which is in equilibrium with its ionic components in solution.
Chemists have made use of these and similar reagents to effect the mild conversion of alcohols to alkyl halides with clean inversion of configuration. As with other OH substitution reactions, an inherently poor leaving group hydroxide anion is modified to provide a better leaving group, the stable compound triphenylphosphine oxide. Two such reactions are shown in the following diagram.
In this way even sluggish alcohols that are prone to rearrangement e. The instability of vicinal diiodides relative to their double bond analogs, is the driving force for a novel transformation of vic-glycols to their corresponding alkenes. An example will be displayed by clicking on these equations.
The allylic rearrangement observed in thionyl chloride is similarly avoided by using triphenylphosphine dichloride, or alternatively, by a two step procedure by way of a sulfonate ester. Click on the diagram a second time for an example. The Japanese chemist, O. Mitsunobu, devised a general and exceptionally versatile variant of hypervalent phosphorous chemistry that has been applied to wide selection of alcohols. This method, which now carries his name, uses a reagent mixture consisting of triphenylphosphine, diethyl azodicarboxylate DEAD and a moderate to strong acid.
The steps leading to hydroxyl substitution are outlined in the following diagram. It should be noted that the nucleophile involved in the final S N 2 substitution may be the conjugate base of the acid component or a separate species. This application usually employs benzoic acid or a benzoate salt, and the resulting configurationally inverted ester is then hydrolyzed to the epimeric alcohol. An example of this procedure will be displayed by clicking on the diagram.
In addition to effecting configurational inversion of carbinol sites, the Mitsunobu reaction has also been used to introduce the azide precursor of amines and for the intramolecular preparation of cyclic ethers.
Examples are shown below. Ether Protective Groups. Thanks to their relative lack of chemical reactivity, ethers have proven to be useful protective groups for alcohols and phenols. As outlined in the following diagram, many ether protective groups have been introduced to serve this purpose. Most of these are prepared by acid-catalyzed addition to an alkene or by Williamson alkylation by a suitable alkyl halide.
Acronyms are used for common protective groups, an example being the THP tetrahydropyranyl ethers prepared from dihydropyran DHP , as shown at top left. Whenever a protective or blocking group is used to facilitate a synthetic operation, it normally must be removed once the operation is complete. In this respect it is useful to have an assortment of protective groups for which different chemical conditions accomplish this cleavage.
Show the products of the reactions of each of the ylides you made in Problem CO This is when things really get interesting. It turns out that one P-O bond just isn't enough. The phosphorus is so oxophilic that it takes the oxygen atom all to itself, pulling it right out of the molecule.
It probably doesn't hurt that the four-membered ring is pretty strained, so it is motivated to decompose but be careful: there are plenty of stable four- and even three-membered rings in nature. The arrows shown in the decomposition of the four-membered ring called a betaine are just meant to keep track of electrons; there isn't a true nucleophile and electrophile in this step.
Instead this step may resemble a pericyclic reaction, which is covered in another section. There isn't much doubt that it is a double bond; it is stronger and shorter than a P-O single bond. However, quantum mechanical calculations indicate that the phosphorus can't form a pi bond. This double bond is different than other double bonds you have seen. For that reason, some people prefer to draw this compound as an ylide, too, with a positive charge on the phosphorus, a single bond, and a negative charge on the oxygen.
The phosphorus oxide compound forms, leaving behind an alkene. Alkenes are very common in nature, and this reaction has frequently been used to make interesting alkene-containing compounds for further use or study. The juvenile hormone of the cecropia moth caterpillar JH-1, below is a regulatory hormone used to control the organism's development by preventing it from pupating until conditions are right.
Synthesis of insect hormones is often undertaken in order to control insect populations. Fill in the missing reagents and reaction products. Sulfur ylides are also good nucleophiles for aldehydes and ketones.
However, the unusual stability of the phosphorus-oxygen bond does not have a similar analogue in sulfur chemistry. Sulfur ylides are formed in a manner very similar to phosphorus ylides.
Show, with arrows, the mechanism for formation of the sulfur ylide above. Once formed, sulfur ylides react with aldehydes or ketones. Like phosphorus ylides, the reaction starts out just like any other nucleophile, but a second step takes a very different direction. Pirnot, M. Kunishima, M. Babier-type reactions of aryl halides with ketones by samarium diiodide. Sugimoto, O. Therkelsen, F. Hatano, M. Zinc II -catalyzed addition of grignard reagents to ketones.
Zong, H. Added-metal-free catalytic nucleophilic addition of grignard reagents to ketones. Gao, F. A simple and efficient copper oxide-catalyzed Barbier—Grignard reaction of unactivated aryl or alkyl bromides with ester.
Tetrahedron Lett. Zhou, F. The Barbier-Grignard-type arylation of aldehydes using unactivated aryl iodides in water. Sakai, M. Rhodium-catalyzed addition of organoboronic acids to aldehydes. Tetsuya, Y. Palladium-catalyzed addition of arylboronic acids to aldehydes. Article Google Scholar. Liao, Y. Huang, R. Alkynes as activators in the nickel-catalysed addition of organoboronates to aldehydes.
Orthoplatinated Triarylphosphite as a highly efficient catalyst for addition reactions of arylboronic acids with aldehydes: low catalyst loading catalysis and a new tandem reaction sequence. Tomita, D. Nucleophilic activation of alkenyl and aryl boronates by a chiral Cu I F complex: catalytic enantioselective alkenylation and arylation of aldehydes. Asian J. Zou, T. FeCl3-catalyzed 1,2-addition reactions of aryl aldehydes with arylboronic acids. Oi, S. Rhodium-catalysed arylation of aldehydes with arylstannanes.
Li, C. Grignard-type carbonyl phenylation in water and under an air atmosphere. Rhodium-catalyzed addition of phenylmethyldifluorosilane to aldehydes. Organometallics 20 , — Fujii, T. Rhodium-catalyzed addition of aryl- and alkenylsilanediols to aldehydes. Synlett 2 , — Yang, L. Grignard-type arylation of aldehydes via a rhodium-catalyzed C-H activation under mild conditions.
Zheng, J. Synthesis and decarboxylative Wittig reaction of difluoromethylene phosphobetaine. Conversion between difluorocarbene and difluoromethylene ylide. Deng, X. Difluoromethylation and gem-difluorocyclopropenation with difluorocarbene generated by decarboxylation. Cristau, H. Hartley Frank R.
Google Scholar. Holmes, R. Quin Louis D. Marsden, S. Organic synthesis: the Wittig reaction cleans up. Zaragoza, F. One-step conversion of alcohols into nitriles with simultaneous two-carbon chain elongation. Cyanomethyl trimethylphosphonium iodide as a reagent with a dual mode of action. Ye, L. Wang, P. Double [gamma]-alkylation of allylic phosphorus ylides: a unique access to oxa-bicyclic[3.
Zhang, Y. Reactive, dicationic electrophiles: electrophilic activation involving the phosphonium group. Blakemore, P.
Knochel Paul Elsevier Ltd. Zhang, L. Fenton, G. Part V. The mechanism of thermal decomposition of quaternary phosphonium hydroxides. Zanger, M. Kinetic study of the decomposition of quaternary phosphonium hydroxides. McEwen, W. Mechanisms of substitution reactions at phosphorus. The Wittig reaction and the decomposition of quaternary phosphonium hydroxides.
A kinetic study of the decomposition of quaternary phosphonium hydroxides. Marsi, K. Alkaline cleavage reactions of tetraalkylphosphonium salts. Allen, D. The alkaline hydrolysis of some cyclic phosphonium salts: ring-opening and ring-expansion reactions. C Org. Hawes, W. Alkaline hydrolysis of phosphonium salt with retention of configuration at phosphorus.
Dawber, J. Kinetics of alkaline hydrolysis of quateranry phosphonium salt. The influence of protic and aprotic solents on the hydrolysis of alkyl phenylaphosphonium salt. Phosphorus, Sulfur Silicon Relat. The alkaline hydrolysis of some tri- 2-thienyl phosphonium salts. Inductive effects on the rate of nucleophilic attack at phosphorus. Songstad, G. Kinetic study of the reaction between phosphonium compounds and hydroxyl respectively alkoxides ions.
Acta Chem. Wittig, G. Darstellung und eigenschaften des pentaphenyl-phosphors.
0コメント