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基础有机化学-含硫和含磷化合物
2012-12-17 12:01:05 来源:有机化学网 浏览:55312


Sulfur and Phosphorus Compounds

Sulfur and Phosphorus Compounds

1. Nucleophilicity of Sulfur Compounds

Sulfur analogs of alcohols are called thiols or mercaptans, and ether analogs are called sulfides. The chemical behavior of thiols and sulfides contrasts with that of alcohols and ethers in some important ways. Since hydrogen sulfide (H2S) is a much stronger acid than water (by more than ten million fold), we expect, and find, thiols to be stronger acids than equivalent alcohols and phenols. Thiolate conjugate bases are easily formed, and have proven to be excellent nucleophiles in SN2 reactions of alkyl halides and tosylates.

R–S(–) Na(+)   +   (CH3)2CH–Br      (CH3)2CH–S–R   +   Na(+) Br(–)

Although the basicity of ethers is roughly a hundred times greater than that of equivalent sulfides, the nucleophilicity of sulfur is much greater than that of oxygen, leading to a number of interesting and useful electrophilic substitutions of sulfur that are not normally observed for oxygen. Sulfides, for example, react with alkyl halides to give ternary sulfonium salts (equation # 1) in the same manner that 3º-amines are alkylated to quaternary ammonium salts. Although equivalent oxonium salts of ethers are known, they are only prepared under extreme conditions, and are exceptionally reactive. Remarkably, sulfoxides (equation # 2), sulfinate salts (# 3) and sulfite anion (# 4) also alkylate on sulfur, despite the partial negative formal charge on oxygen and partial positive charge on sulfur.

2. Oxidation States of Sulfur Compounds

Oxygen assumes only two oxidation states in its organic compounds (–1 in peroxides and –2 in other compounds). Sulfur, on the other hand, is found in oxidation states ranging from –2 to +6, as shown in the following table (some simple inorganic compounds are displayed in orange).

Try drawing Lewis-structures for the sulfur atoms in these compounds. If you restrict your formulas to valence shell electron octets, most of the higher oxidation states will have formal charge separation, as in equation 2 above. The formulas written here neutralize this charge separation by double bonding that expands the valence octet of sulfur. Indeed, the S=O double bonds do not consist of the customary σ & π-orbitals found in carbon double bonds. As a third row element, sulfur has five empty 3d-orbitals that may be used for p-d bonding in a fashion similar to p-p (π) bonding. In this way sulfur may expand an argon-like valence shell octet by two (e.g. sulfoxides) or four (e.g. sulfones) electrons. Sulfoxides have a fixed pyramidal shape (the sulfur non-bonding electron pair occupies one corner of a tetrahedron with sulfur at the center). Consequently, sulfoxides having two different alkyl or aryl substituents are chiral. Enantiomeric sulfoxides are stable and may be isolated.

Thiols also differ dramatically from alcohols in their oxidation chemistry. Oxidation of 1º and 2º-alcohols to aldehydes and ketones changes the oxidation state of carbon but not oxygen. Oxidation of thiols and other sulfur compounds changes the oxidation state of sulfur rather than carbon. We see some representative sulfur oxidations in the following examples. In the first case, mild oxidation converts thiols to disufides. An equivalent oxidation of alcohols to peroxides is not normally observed. The reasons for this different behavior are not hard to identify. The S–S single bond is nearly twice as strong as the O–O bond in peroxides, and the O–H bond is more than 25 kcal/mole stronger than an S–H bond. Thus, thermodynamics favors disulfide formation over peroxide. 
Mild oxidation of disufides with chlorine gives alkylsulfenyl chlorides, but more vigorous oxidation forms sulfonic acids (2nd example). Finally, oxidation of sulfides with hydrogen peroxide (or peracids) leads first to sulfoxides and then to sulfones.

The nomenclature of sulfur compounds is generally straightforward. The prefix thio denotes replacement of a functional oxygen by sulfur. Thus, -SH is a thiol and C=S a thione. The prefix thia denotes replacement of a carbon atom in a chain or ring by sulfur, although a single ether-like sulfur is usually named as a sulfide. For example, C2H5SC3H7 is ethyl propyl sulfide and C2H5SCH2SC3H7 may be named 3,5-dithiaoctane. Sulfonates are sulfonate acid esters and sultones are the equivalent of lactones. Other names are noted in the table above.



3. Oxidation of Alcohols by DMSO

The conversion of 1º and 2º-alcohols to aldehydes and ketones is an important reaction which, in its simplest form, can be considered a dehydrogenation (loss of H2). By providing an oxygen source to fix the product hydrogen as water, the endothermic dehydrogenation process may be converted to a more favorable exothermic one. One source of oxygen that has proven effective for the oxidation of alcohols is the simple sulfoxide solvent, DMSO. The reaction is operationally easy: a DMSO solution of the alcohol is treated with one of several electrophilic dehydrating reagents (E). The alcohol is oxidized; DMSO is reduced to dimethyl sulfide; and water is taken up by the electrophile. Due to the exothermic nature of the reaction, it is usually run at -50 ºC or lower. Co-solvents such as methylene chloride or THF are needed, since pure DMSO freezes at 18º. The reaction of oxalyl chloride with DMSO may generate chlorodimethylsulfonium chloride which then oxidizes the alcohol (Swern Oxidation). Alternatively, a plausible general mechanism for this interesting and useful reaction is drawn below.

Because so many different electrophiles have been used to effect this oxidation, it is difficult to present a single general mechanism. Most of the electrophiles are good acylating reagents, so it is reasonable to expect an initial acylation of the sulfoxide oxygen. (The use of DCC as an acylation reagent was described elsewhere.) The electrophilic character of the sulfur atom is enhanced by acylation. Bonding of sulfur to the alcohol oxygen atom then follows. The remaining steps are eliminations, similar in nature to those proposed for other alcohol oxidations. In some cases triethyl amine is added to provide an additional base. Three examples of these DMSO oxidations are given in the following diagram. Note that this oxidation procedure is very mild and tolerates a variety of other functional groups, including those having oxidizable nitrogen and sulfur atoms.

4. Nucleophilicity of Phosphorus Compounds

Phosphorous analogs of amines are called phosphines. The chemistry of phosphines and the related phosphite esters is dominated by their strong nucleophilicity and reducing character. The nucleophilicity of trivalent phosphorus results in rapid formation of phosphonium salts when such compounds are treated with reactive alkyl halides. For example, although resonance delocalization of the nitrogen electron pair in triphenylamine, (C6H5)3N, renders it relatively unreactive in SN2 reactions, the corresponding phosphorus compound, triphenylphosphine, undergoes a rapid and exothermic reaction to give a phosphonium salt, as shown below in the first equation. Phosphite esters react in the same manner, but the resulting phosphonium salts (shaded box) are often unstable, and on heating yield dialkyl phosphonate esters by way of a second SN2 reaction (equation 2 below).



5. Oxidation States of Phosphorus Compounds

The difference in oxidation states between nitrogen and phosphorus is less pronounced than between oxygen and sulfur. Organophosphorus compounds having phosphorus oxidation states ranging from –3 to +5, as shown in the following table, are well known (some simple inorganic compounds are displayed in green). As in the case of sulfur, the P=O double bonds drawn in some of the formulas do not consist of the customary sigma & pi-orbitals found in carbon double bonds. Phosphorus is a third row element, and has five empty 2d-orbitals that may be used for p-d bonding in a fashion similar to p-p (π) bonding. In this way phosphorus may expand an argon-like valence shell octet by two electrons (e.g. phosphine oxides).



6. Phosphorus Compounds as Reducing Agents

Trivalent phosphorus is easily oxidized. In contrast with ammonia and amines, phosphine and its mono and dialkyl derivatives are pyrophoric, bursting into flame on contact with the oxygen in air. The affinity of trivalent phosphorus for oxygen (and sulfur) has been put to use in many reaction systems, three of which are shown here. The triphenylphosphine oxide produced in reactions 1 & 3 is a very stable polar compound, and in most cases it is easily removed from the other products. Reaction 2 is a general formulation of the useful Corey-Winter procedure for converting vicinal glycols to alkenes.

Triphenylphosphine is also oxidized by halogens, and with bromine yields dibromotriphenylphosphorane, a crystalline salt-like compound, useful for converting alcohols to alkyl bromides. As in a number of earlier examples, the formation of triphenylphosphine oxide in the irreversible SN2 step provides a thermodynamic driving force for the reaction.


Phosphorus & Sulfur Ylides

Phosphorus and Sulfur Ylides

1. Preparation of Ylides

It has been noted that dipolar phosphorus and sulfur oxides are stabilized by p-d bonding. This may be illustrated by a resonance description, as shown here.

This bonding stabilization extends to carbanions alpha to phosphonium and sulfonium centers, and the zwitterionic conjugate bases derived from such cations are known as ylides. Approximate pKa's for some ylide precursors and related compounds are provided in the following table. The acidic hydrogen atoms are colored red. By convention, pKa's are usually adjusted to conform to the standard solvent water; however, in practice, measurements of very weak acids are necessarily made in non-aqueous solvents such as DMSO (dimethyl sufoxide). The green numbers in the table represent DMSO measurements, and although these are larger than the aqueous approximations, the relative order is unchanged. Note that DMSO itself is the weakest acid of those shown.

Compound (C6H5)3P(+)–CH3 I(–) (CH3)3S(+) I(–) (CH3)3S(+)=O I(–) (CH3)2S=O (CH3)2S(=O)2 CH3-P(OCH3)2=O
Name methyltriphenylphosphonium
iodide
trimethylsulfonium
iodide
trimethylsulfoxonium
iodide
dimethyl sulfoxide dimethyl sulfone dimethyl methylphosphonate
pKa
DMSO
17
22
20
25
15
18
30
35
26
31
25
31

Some characteristic preparations of ylide reagents are shown below. Very strong bases, such as butyl lithium, are required for complete formation of ylides. Sodium hydride (NaH), another powerful base, is insoluble in most solvents, but its reaction with DMSO (the weakest acid in the table) generates a strong conjugate base, CH3)S(=O)CH2(–) Na(+), known as dimsyl sodium. This soluble base is widely used for the generation of ylides in DMSO solution. 

The ylides shown here are all strong bases. Like other strongly basic organic reagents, they are protonated by water and alcohols, and are sensitive to oxygen. Water decomposes alkylidenephosphoranes to hydrocarbons and phosphine oxides, as shown. Oxygen cleaves these ylides in a similar fashion, the alkylidene moiety being converted to a carbonyl compound.

R3P=CR'2   +   H2O      [ R3P(OH)–CHR'2 ]      R3P=O   +   R'2CH2
R3P=CR'2   +   O2      R3P=O   +   R'2C=O

2. Reactions of Ylides

The most important use of ylides in synthesis comes from their reactions with aldehydes and ketones, which are initiated in every case by a covalent bonding of the nucleophilic alpha-carbon to the electrophilic carbonyl carbon. Alkylidenephosphorane ylides react to give substituted alkenes in a transformation called the Wittig reaction. This reaction is illustrated by the first three equations below. In each case the new carbon-carbon double bond is colored blue, and the oxygen of the carbonyl reactant is transferred to the phosphorus. The Wittig reaction tolerates epoxides and many other functional groups, as demonstrated by reaction # 1. The carbanionic center may also be substituted, as in reactions # 2 & 3. A principal advantage of alkene synthesis by the Wittig reaction is that the location of the double bond is absolutely fixed, in contrast to the mixtures often produced by alcohol dehydration. With simple substituted ylides Z-alkenes are favored (reaction # 2).
The fourth equation shows a characteristic reaction of a sulfur ylide. Again, the initial carbon-carbon bond is colored blue, but subsequent steps lead to an epoxide product rather than an alkene.

     


Two other examples of Wittig-like reactions may be seen by clicking the "More Reactions" button. Reaction # 5 illustrates a double Wittig reaction, using a dialdehyde reactant (colored orange). Because of the additional allylic stabilization of the ylide group, the new double bonds (colored blue) have an E-configuration, in contrast to the Z-configuration favored by unstabilized ylides (equation 2). Reaction # 6 shows a related synthesis that employs a phosphonate enolate base as the nucleophile. This is known as the Horner-Wadsworth-Emmons reaction. Here, as with the Wittig reaction, the formation of a stable phosphorus oxygen bond in the phosphate product provides a driving force for the transformation. Again, stabilization of the ylide-like carbanion leads to an E-configuration of the product double bond. These remarkable and useful changes can be explained by the mechanisms displayed by clicking the "Show Mechanism" button.
Following the initial carbon-carbon bond formation, two intermediates have been identified for the Wittig reaction, a dipolar charge-separated species called a betaine and a four-membered heterocyclic structure referred to as an oxaphosphatane. Cleavage of the oxaphosphatane to alkene and phosphine oxide products is exothermic and irreversible. Depending on the stability of the starting ylide, the betaine may be formed reversibly and this will ultimately influence the stereochemistry of the alkene product.
In contrast to the phosphorus ylides and related reagents, reactions of sulfur ylides with carbonyl compounds do not usually lead to four-membered ring species analogous to oxaphosphatanes. The favored reaction path is therefore an internal SN2 process that leads to an epoxide product. The sulfur leaves as dimethyl sulfide. Additional examples of sulfur ylide reactions, illustrating differences in the reactivity of dimethylsulfonium methylide and dimethyloxosulfonium methylide, are given in the following diagram. Of the two, the oxosulfonium ylide is less reactive and is thought to add reversibly to carbonyl groups, eventually forming the thermodynamically favored product.


Other Acylation Reagents and Techniques

Specialized Acylation Reagents and Techniques

Because acylation is such an important and widely used transformation, many novel techniques have been developed for this purpose. A few of these are described here.

1.   Carbodiimides and Related Reagents

The ideal acylating reagent would be a carboxylic acid, but the acids themselves are relatively unreactive with nucleophiles. A simple solution to this inactivity, as noted earlier, was to convert the carboxylic acid to a more reactive derivative such as an acyl chloride or anhydride. A less extreme alternative procedure, often used in difficult cases, makes use of reagents which selectively activate a carboxyl group toward nucleophilic substitution. Two such reagents are dicyclohexylcarbodiimide (DCC) and carbonyldiimidazole (Staab's reagent). The following equations provide examples of their use in the preparation of esters, amides, anhydrides and peresters. Indeed, LAH reduction of the imidazolide intermediate generated by the Staab reagent provide