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CHEM 767 Chem Info Retrieval Final Project

** Synthesis and Applications of Nitrate Esters ** Nitrate esters are a type of ester formed mainly from inorganic acids. The general formula of a nitrate ester is R-ONO2. The nitrate functionality of the nitrate ester is overall neutral. This is because that one of the oxygens is bound the R group and the nitrogen, an oxygen double bound to the nitrogen, and another oxygen with a negative charge. The nitrogen is positively charged because it has four bonds on it. So the nitrate grouping has a positive and negative charge, thus overall making it neutral. As most classes of organic compounds, nitrate esters may be synthesized through a variety of ways and have a large variety of applications. One of the very first ways that nitrate esters were synthesized is by generation of the nitronium ion. The nitronium ion has the structure NO2+, and is synthesized by mixing equimolar volumes of concentrated nitric acid and concentrated sulfuric acid(1). The –OH of the nitric acid grabs one protons of the sulfuric acid forming bisulfate and the protonated nitric acid. The negative oxygen crashes down, forms a double bond with the nitrogen, and the water leaves yielding the nitronium ion. The newly formed nitronium ion is then added to the alcohol of interest. The oxygen molecule of the alcohol will attack the positive nitrogen of the nitronium ion and for the protonated for of the nitrate ester. Finally, the bisulfate generated from the formation of the nitronium ion will rip off the final proton, reform sulfuric acid, and the final nitrate ester will be formed. Synthesis of nitrate esters in this fashion has had average yields, 60-70%, due to the fact of detrimental side reactions. Having concentrated acids such as nitric or sulfuric acids in the presence of alcohols because of the hydroxy grouping be protonated. Depending on the alcohol, SN1 and E1 reactions are viable. This all depends on the stability of the carbocation generated. It the molecule is highly substituted, the carbocation will be very stable and will proceed through this reaction mechanism. This reaction has been one of the more traditional ways in making nitrate esters such as nitrocellulose and nitroglycerin. One of the major uses of nitrate esters is their energetic capability. As you know, both nitroglycerin(2) and nitrocellulose(3) are very explosive and research has been done in making other explosives from nitrate esters. Some explosives couple multiple nitro groupings with nitrate esters to make more explosive materials. One of the compounds studied was a 1,3,5-trinitro toluene type compound, but instead of a methyl, they have replaced it with a 2-nitroxyethylnitramino grouping(4). Synthesizing this compound increases the explosive character dramatically due to the added nitro and nitrate ester grouping. Another group has done the opposite, having 4 nitrate ester groupings and two nitro groupings. The Chavez group made a very energetic nitrate ester, pentaerythritol tetranitrate(5) (PETN). This compound was determined to have a large explosive potential and the impact, spark, and frictional ignition values were calculated. Methods have also been developed for the detection of compounds from the residues left behind from the explosion. Any type of nitrate ester residue will leave behind trace amounts of (NO2-). To the residue, they add one of two reagents B or C. Reagent B contains some type of hydroxide base. The mixture is then heated, and reagent C is added. Reagent C is some type of acid. After all these conditions are applied, the material will become luminescent and will be visible under black light(6). If the materials are not a nitrate ester, then it will not be luminescent under these conditions. Use of the nitronium ion is a very efficient way for synthesizing nitrate esters, but the conditions are too harsh for most alcohols. As said before, mainly primary and some secondary alcohols may be converted to nitrated esters without having any side reactions. An alternative method to nitrating alcohols is through the use of a mixed anhydride(7). A mixed anhydride is similar to an anhydride except for the fact that one of the two carbonyls is some sort of heteroatom double bonded to an oxygen. The classic functionality of a mixed anhydride is R-(C=O)-O-(N=O)-R’. For synthesis on nitrate esters, the mixed anhydride used is acetyl nitrate. Acetyl nitrate is synthesize by mixing equimolar quantities of acetic anhydride and nitric acid (fuming, >95%). The acetyl nitrate is formed by having the oxygen of the acetic anhydride becoming protonated by the nitric acid, yielding a nitrate anion. Next, the nitrate anion attacks of the carbonyls and a molecule of acetic acid is released, thus forming the mixed anhydride(8). In the reaction chamber some kind of base, usually sodium carbonate, is used in order to neutralize the acetic acid formed from the reaction and any excess nitric acid. After the mixed anhydride has been made and any excess acid neutralized, the alcohol to be nitrated is added. The oxygen of the alcohol will attack the nitrogen and an acetate will be knocked off. After that, the acetate will rip off the proton f the protonated oxygen. Once again, the acetic acid generated will be neutralized by the base present in the solution(9). Yields of these reactions have been know to be very high, 85-97%. This is due to the fact that the conditions are much milder than that of the nitronium ion. Another reason is that a very reactive species is generated which adds to the amount of nitrate ester synthesized. Finally, prevention of side reactions by neutralized and concentrated acids or other acids generated by the reaction will also add to the yield. This reaction has been the major reaction used to synthesize nitrate for the past few decades. While the synthesis of nitrate esters via acetic anhydride and fuming nitric acid works well, the nitration conditions are very harsh and may catalyze side reactions such as dehydrations. Another method of synthesizing nitrate esters is with the combination of lithium nitrate, trifluoroacetic anhydride (TFAA), and sodium carbonate in acetonitrile(10). As you can see, there are no concentrated acids present, so there will be a less chance of any detrimental side reactions. For this synthesis to be initiated, the lithium nitrate and TFAA are mixed together in acetonitrile for an hour. Mixing of these two species will create a reactive mixed anhydride of a trifluoroacetyl nitrate species. Even though a mechanistic study has not been performed yet, it is believed that the mechanism for this reaction parallels that of the acetic anhydride and fuming nitric acid. The nitrate anion will attack the a carbonyl of the TFAA and a trifluoroacetate will leaving, forming the trifluoroacetyl nitrate. With the trifluoroacetate leaving, this can cause side reactions by having the trifluoroacetate attacking a starting material or it picking up a proton and forming trifluoroacetic acid. Initial attempts were made to synthesize nitrate esters by simply mixing the mixed anhydride with the alcohol in dichloromethane. This is performed as biphase reaction due to the insolubility of the lithium nitrate in methylene chloride. Under these conditions, the nitrated product was barely formed and the trifluoroacetylated product was synthesized. This is an indication that the mixed anhydride is not being formed, and the TFAA is transforming the alcohol instead. The reaction was then attempted in solvents that lithium nitrate was soluble in, THF and acetonitrile. In both these solvents, the reaction yielded up to a 3:2 ration between nitrate and trifluoroacetylated products. Even though a large amount of nitrated products was synthesized, there was still a significant amount of trifluoroacetylated product. The Gavrila group determined that trifluoroacetic acid was generated from reaction of the alcohol and the mixed anhydride. In order to compensate for the generation of the trifluoroacetic acid, solid sodium carbonate was added to immediately neutralize and acid formed. Nitration with sodium carbonate present provided a 91% yield of the nitrate ester. Several other alcohols were converted to their nitrate ester analogues under the same conditions with very high yields. If any strong nucleophiles are present in the solution, the nitrate ester may undergo a decomposition, elimination, or a substitution reaction. The two previous syntheses were performed by generation of a reactive mixed anhydride. Both these ways work very well, but other methods of nitration need to be examined. In this next reaction, the hydroxy grouping of the alcohol is first converted to a chloroformate, then a nitratocarbonate, and finally a nitrate ester(11). This synthesis utilizes phosgene (COCl2) and silver nitrate (AgNO3). The chloroformate is formed by reaction of the starting alcohol with phosgene. This is carried out by addition of the alcohol dropwise to a refluxing phosgene solution. The phosgene is susceptible to di substitution, but in order to avoid that the phosgene is in a large excess when compared to the alcohol. This pretty much guarantees that the phosgene will only be mono substituted and not di substituted(12). There is a small statistical chance that the phosgene will be di substituted, but with the large excess it is virtually eliminated. After the chloroformate has been extracted and purified, it is immediately treated with silver nitrate. Here the nitrate will attack the carbonyl of the chloroformate and the chloride will be knocked off forming the nitratocarbonate. The chloride that is formed from the substitution is then grabbed by the silver cations and forms silver chloride (solid). The generation of the silver chloride precipitate can be used to quantitatively measure the progress of the reaction. The nitratocarbonate formed is very unstable and undergoes a decomposition reaction via a SN’ mechanism. The nitratocarbonate breaks apart, expels carbon dioxide, and forming a tight ion pair between the alkoxide (R-O-) and the newly formed nitronium (NO2+). Since the alkoxide and the nitronium are so close together, the negative charge on the oxygen of the alkoxide will attack the positively charged nitrogen and form the nitrate ester. One of the major driving forces of this reaction is the formation of very stable products, carbon dioxide and the nitrate ester. Another way that the amount of nitrate ester can be quantified is through vapor chromatography(13). With this, they can actually measure the amount of carbon dioxide formed from the decomposition of the nitratocarbonate. One other thing that was found with the vapor chromatography was the starting alcohol. The alcohol is probably made due to some hydrochloric acid being generated when the chloroformate was made. The acid generated may cause the nitratocarbonate to be protonated and reform the starting alcohol. This reaction has shown to synthesize nitrate esters at very high yields. One of the major setbacks of this reaction is the use of phosgene, a very reactive compound and has been used in wars as a chemical pneumonia inducing agent. On a positive note, this reactions has two separate ways to quantify the amount of nitrate ester formed, silver chloride and carbon dioxide. Both quantities should give similar results to the amount of nitrate ester. Another method of nitration that has been practically unstudied, is with the use of nitryl fluoride. Nitryl fluoride has the chemical structure of FNO2(14). It is synthesized by the reaction of fluorine gas and dinitrogen tetroxide. Here both the fluorine and the dinitrogen tetroxide are placed in a chamber under high pressure and temperature, and the nitryl fluoride is made with good yields. After the nitryl fluoride is separated from the other gases, it is used for the nitration. For the nitration, the alcohol to be nitrated is placed in anhydrous methanol with potassium fluoride(15). The potassium fluoride is used to neutralize any hydrofluoric acid formed by formation of potassium bifluoride, which is insoluble in methanol. Formation of the potassium bifluoride is an added bonus because you can quantitatively measure how much was formed, and you can calculate how much nitrate ester was formed. Finally, nitryl fluoride is bubbled into the solution at -20 to -30 oC with vigorous stirring(16). This reaction works by having the alcohol oxygen attacking the nitrogen of the nitryl fluoride, and the fluorine leaves. The resulting fluorine grabs the proton from the hydrogen on the –OH forming hydrofluoric acid. As soon as the hydrofluoric acid is formed, it will be neutralized. The hydrofluoric acid must be neutralized immediately in order to prevent any detrimental side reactions with the starting alcohol. Nitrations under these conditions were performed with several alcohols ranging from ethanol to cyclohexanol. Yields for these reactions ranged from at least 85% to about 96%. Very high yields and a fairly simple synthesis make this reaction very useful and further studies will be made from this initial study. The previous reactions required an alcohol to begin with in order to form a nitrate ester. Now we will look at the synthesis of 1,2-dinitrates from epoxides via dinitrogen pentoxide(17) (N2O5). They attempted to nitrate cyclopentene oxide with the dinitrogen pentoxide and they notice that the major product formed was the //trans// isomer of cyclopentane-1,2-dinitrate. This gives insight into the mechanism of the reaction. In order for this to happen, the dinitrogen pentoxide dissociates ionically into the nitronium ion and a nitrate anion. When this happens, the oxygen of the epoxide attacks the nitronium ion and forms the intermediate. Next the nitrate ion attacks either side of the epoxide ring and performs a ring opening reaction giving the //trans// form of 1,2-dinitrate. Nitration is conducted by dissolving dinitrogen pentoxide in methylene chloride. Next a mixture of the epoxide and methylene chloride is added dropwise to the first solution. Sodium bicarbonate is also added to the solution in order to neutralize and acid generated from the reaction. With this reaction, compounds with multiple nitrate groupings can be made. One example that they used was taking 1,3-butene-dioxide and adding it to over two equivalents of the dinitrogen pentoxide. This reaction showed two ring opening epoxidations with this yielding 1,2,3,4-butane-tetranitrate. The yields for this reaction can vary depending on how many nitrate ester groups are formed in the molecule. For reactions that form only two nitrate ester groupings, yields are about 75-80%. As you make more and more nitrate groups the yield will slowly decrease. It seems that about for every one nitrate ester grouping you add, the yield is about 85-90%. So the more nitrate ester groupings you make, the overall yield will roughly be 0.87n where n is the number of nitrate ester groupings. An additional way to synthesize nitrate esters from epoxides, is by using Bi(NO3)3(18). This reagent primarily forms b- hydroxy nitrate esters. In these types of reactions, the oxygen of the epoxide will attack the bismuth and kick off a nitrate. The nitrate that was just released will attack either side of the epoxide ring and open it(19). Open the ring opening of the epoxide, the hydrogen will become protonated, must likely from water in the solution and the Bi(NO3)2- will grab the newly formed hydroxide and form Bi(NO3)2OH. This reaction has also been shown to brominates with BiBr3 and chlorinate with BiCl3. Nitrate esters have also been synthesized from alkyl halides with the use of silver nitrate(20). This is a very simple reaction to perform. The only setback is the expensive materials needed. Silver nitrate is about three dollars per gram, which is much more expensive than other reagents previously stated. For each reaction, the procedures call for about twenty grams of silver nitrate. So for each synthesis, you need at least sixty dollars to perform one nitration. If funding is not an issue, than this reaction will produce nitrate esters with the least amount of effort. In these reactions, the nitrate ion will attack the carbon with the halide attached. The halides that work the best are chloride and bromide. This reaction seems to proceed in a SN2 fashion, and kicking off the halide. The free halide will combine with the silver present in the solution and precipitate out as either silver chloride or silver bromide. Once again, you can quantitatively measure the amount of silver halide salt and direct determine the amount of nitrate ester that was made. Synthesis of nitrate esters has grown drastically from when they were first discovered. Now we have dozens of various methods to synthesize them depending on the conditions and the structure of the final products. As you saw, we have moved way past simply mixing equimolar quantities of nitric and sulfuric acid to exotic reagents such as Bi(NO3)3 and trifluoroacetyl nitrate. Overall, these syntheses provide nitrate esters in very high yields.


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