CHM2123_2023_Hydrazone

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H IGHWAY TO THE HYDRAZONE – T HE IDENTIFICATION OF UNKNOWN CARBONYLS S ARA M UDRY , F RANÇOIS M AGNAN While a melting point analysis was an analytical technique of interest in the past for confirming the identity of a reaction’s product, it was inherently limited to products that were already solid at room temperature. As a work-around, chemists would further react liquid products with a derivatizing agent to convert the product into a solid analogue, which could then be analyzed and compared to the reported value. For this experiment, you will perform such an analysis with the help of 2,4-dinitrophenylhydrazine (DNPH), a derivatizing agent for ketones and aldehydes. You are tasked with identifying an unknown carbonyl derivative from a select list of possible reagents. By reacting your unknown carbonyl with DNPH, you will produce the corresponding hydrazone, which you will purify via a quick recrystallization, By measuring the melting point of your purified product and comparing to a list of known values, you will then be able to ascertain the identify of the carbonyl derivatives that was provided to you.

2,4-Dinitrophenylhydrazine (DNPH) is an organic mol- ecule that once enjoyed a certain popularity in the synthetic lab due to its unique properties and reactivity that were often exploited for analytical purposes. The hydrazine moiety (–NH–NH 2 ) is a nucleophile that will readily react with elec- trophilic carbonyls ( e.g. aldehydes and ketones) to form the corresponding hydrazone (Fig. 1). 1. Pedagogical • Apply common fundamental laboratory techniques. • Perform a synthetic organic transformation. • Perform a recrystallization, a useful purification technique for organic solids. • Relate the concepts of structure, purity, and melting point. 2. Experimental • React a mystery carbonyl derivative with DNPH to convert it into the corresponding hydrazone. • Purify the product by recrystallization. • Ascertain the identity and purity of the final product via TLC and melting point analysis. OBJECTIVES Also available... KEY TERMS • Hydrazine • Hydrazone • Nucleophilic acyl substitution KEY VIDEOS • Reflux assembly • Vacuum filtration • Recrystallization • Thin-Layer Chromatography • Melting Point HYDRAZONES AS USEFUL REAGENTS Such a reaction is in-fact fairly unique to aldehydes and ketones, since other carbonyl derivatives ( e.g. amides, car- boxylic acids, esters) are not sufficiently electrophilic due to conjugation effects. For that reason, DNPH was often used in the first half of the 20 th century as a key reagent in analytical schemes. On one hand, DNPH can be useful for the qualitative detection of carbonyl derivatives: in con- tact with reactive carbonyls, DNPH will rapidly form brightly colored hydrazones that readily precipitate. In that context, the formation of a solid upon treating the solution of an unknown molecule with DNPH can be used as a presumptive test for the presence of a ketone or an aldehyde motif in the molecule in question (or the absence of such motifs, if no precipitate is observed). Figure 1 – The reaction of 2,4-dinitrophenylhydrazine (DNPH) with a reactive carbonyl (aldehyde or ketone) results in the formation of a hydrazone (red). H N NH 2 NO 2 O 2 N R R/H O H N N NO 2 O 2 N R/H R + DNPH Hydrazone

3 The identification of unknown carbonyls THE TRANSFORMATION Alternatively, DNPH was used in the identifi- cation of simple liquid aldehydes and ketones. Whereas a melting point analysis is often used to characterize solids, such an analysis can prove to be more problematic when the substance melts below room temperature! In that regard, simple liquid aldehydes and ketones would instead be identified by converting them to their correspond- ing DNPH-derived hydrazone. Following a recrys- tallization, the product would then be analyzed by melting point: by comparing this value to re- ported values, one could potentially identify a given carbonyl derivative – or, at the very least, narrow the list of possibilities. DNPH is an ideal reagent in such a context, as it rapidly reacts with the un- known carbonyl to form solid products that are readily recrystallized and that possess sharp, re- peatable melting points. Whereasyoudonotlearnofhydrazoneformation in CHM2120, you do learn of a similar reaction – the formation of imines . So similar in fact that the mechanisms for the two reactions are effec- tively identical! An imine is made from the reaction of a primary amine 1 (Fig. 2) with a reactive car- bonyl 2 (again, an aldehyde or a ketone): nucle- ophilic attack of the nitrogen onto the carbonyl forms a tetrahedral intermediate 3 . Intermolecular proton transfer steps eventually lead to the for- mation of 4 , which bears an oxonium (–OH 2 + ), a Figure 2 – a) The formation of an imine is achieved by reacting a primary amine ( 1 ) with a reactive carbonyl ( 2 ) under acidic catalysis. Following nucleophilic attack and proton transfer steps, the resulting amino oxonium ( 4 ) loses a water-molecule, and the carbon atom is stabilized by the neighboring nitrogen’s lone pair of electrons to form the iminium ( 5 ). Loss of a proton forms the resulting imine and regenerates the acid catalyst. B) Similarly to what was seen in a), a hydrazine ( 7 ) reacts with a reactive carbonyl to eliminate a water molecule and form a C=N double bond, resulting in a hydrazone. great leaving group. Upon its departure, the elec- tron-deficient carbon is stabilized by the neighbor- ing nitrogen, who shares its lone pair of electrons to form a C=N double bond iminium 5 , which sub- sequently loses a hydrogen atom to form the neu- tral imine 6 . Such a reaction is usually done in the presence of an acid catalyst, which protonates the initial carbonyl to make it more electrophilic. The formation of the hydrazone is conceptually identical. The initial primary amine is replaced with the hydrazine derivative 7 , which has two nitrogen atoms. In asymmetrically-substituted hy- drazines, one must consider which of the two ni- trogen atoms will perform a nucleophilic attack, which is dependant on the nature of the functional groups attached. In the case of a hydrazine mono- substituted with an aromatic ring, such as in the case of DNPH, the substituted nitrogen has de- creased nucleophilicity by virtue of resonance de- localization of the heteroatom’s lone pair of elec- trons onto the aromatic ring, which does not occur for the terminal nitrogen. For this reason, the ter- minal nitrogen is the most nucleophilic of the two atoms and will undergo the reaction with the re- active carbonyl. The rest of the mechanism is vir- tually identical to what was described above for the imine: attack of the nitrogen unto the carbonyl yields, after a series of intermolecular proton trans- fers, a C=N double bond bridging the two starting materials ( 11 ). Since the C=N group is function- alized with a second nitrogen atom, the resulting molecule is a hydrazone rather than an imine, since the two vary in properties and reactivities. a) b) R 1 NH 2 R 2 R 3 /H O R 2 R 3 /H OH NH 2 HN R 2 R 3 /H OH 2 NH R 1 R 2 R 3 /H NH R 1 R 2 R 3 / H N R 1 + N H NH 2 Ar R 2 R 3 /H O R 2 R 3 /H OH NH 2 R 1 Cat. H + Ar R 2 R 3 /H OH 2 NH HN Ar R 2 R 3 /H NH HN Ar R 2 R 3 /H N HN A r Cat. H + + ± H + ± H + – H + – H + 1 2 3 4 5 6 7 2 8 9 10 11

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Owingtotherelativelylowsolubilityoftheproduct hydrazone, isolating and purifying the product is straightforward. The crude reaction mixture, once cooled, is filtered to isolate the crude product, which is then recrystallized from a mixture of ethanol and acetone. The purified product is isolated once more by vacuum filtration before drying in an oven to remove the last traces of the volatile organic solvents. Following a short cooling period, you will be able to weigh your product to ascertain the yield, then analyze it using the usual combi- nation of thin-layer chromatography and melting point analysis. TLC will allow you to ascertain that your product is distinct from the starting DNPH and sufficiently pure; a melting point analysis will allow you to identify your product by simple com- parison of the melting temperature to a short list of possible derivatives. The identification of unknown carbonyls 4 THE EXPERIMENT For this experiment, you will aim to condense 3.00 mmol of DNPH with an unknown reactive carbonyl derivative provided to you, so as to con- dense them both into the corresponding hydra- zone. Once isolated and purified, you will measure your respective hydrazone’s melting point: based on this value, you should then be able to identify the starting carbonyl derivative that was provided to you. Obviously, such an analysis is compara- tive in nature, and can only be done with the help of reference values, particularly since various car- bonyls can potentially yield hydrazones with very similar melting points. For the current experiment, one of six carbonyl derivatives will be provided to you: their identity, along with the melting point of their corresponding DNPH hydrazone, are listed in table 1. Table 1 – List of possible reactive carbonyls that can be provided to you at the beginning of the experiment, along with the approximate melting point of the corresponding DNPH-based hydrazone. Starting carbonyl Structure Hydrazone’s approximate melting point (°C) 2-Butanone 115 Butanal 130 2-Pentanone 145 3-Pentanone 160 Formaldehyde 170 2- Methylpropanal 190 O H O O O H H O H O

5 The identification of unknown carbonyls C ONDENSING AN ELECTROPHILIC CARBONYL TO ITS CORRESPONDING HYDRAZONE 1. Add DNPH (1.00 eq.), 95% EtOH ([DNPH] = 0.20 M), two drops of con- centrated sulfuric acid and the entire unknown carbonyl sample pro- vided to you to a 100 mL round-bottom flask, along with a stirbar. 2. Assemble the flask into a reflux apparatus, and bring the reaction to a boil for 15 minutes under vigorous stirring. 3. During the reflux, using hexanes and ethyl acetate (~10 mL total, care- fully measured using a small graduated cylinder), develop an eluent for the analysis of the reaction and its product: to that effect, aim for a mix that provides an R f of ~0.25–0.35 for DNPH. Note the composition of the eluent, and use it for the rest of the experiment. 4. Once the 15 minutes period is over, cool the flask in an ice bath for about 5 minutes. Vacuum-filter the chilled mixture to isolate the solid, and rinse it with 2×10 mL portions of 95% ethanol. Pump dry for approx- imately one minute to remove as much liquid as possible. Rxn. Time ~ 30 min Purif. Time ~ 60 min. 12 6 9 3 REAGENTS 2,4-Dinitrophenylhydrazine (DNPH) 95% Ethanol Concentrated H 2 SO 4 Unknown carbonyl 3:1 Ethanol/acetone mixture REACTION Thin-Layer Chromatograhy Melting Point Reflux heating 4. Weigh the dried solid to obtain a crude mass. Transfer the solid into a 125 mL erlenmeyer. 5. Recrystallize the solid in a minimum of 3:1 EtOH/acetone, starting with 15 mL/gram of crude and adding additional solvent in 5/10 mL portions as needed. Once dissolved, cool the mixture to room temperature for 10 minutes, then in a room-temperature water bath (no ice) for 5 minutes. 6. Vacuum-filter the recrystallized mixture with a clean Buchner to isolate the solid, and rinse it with 2×5 mL portions of 95% ethanol. Pump dry for approximately one minute to remove as much liquid as possible. PURIFICATION H N NH 2 NO 2 O 2 N R R/H O H N N NO 2 O 2 N R/H R + cat. H + NMR Spectroscopy 1 H IR Spectroscopy IR Recrystallization

The identification of unknown carbonyls 6 TIPS ANALYSIS 8. Demonstrate the identity and purity of your unknown product using: • TLC : Dissolve a small amount (~0.01 g; the tip of a spatula) in a small volume of dichloromethane (~1–2 mL) in a test tube before spotting on your plate and eluting with the eluent found at step 3. • Melting point analysis : You do not know the expected melting point of your respective product. For that reason, prepare two capillaries from your product with the help of a straw. Analyze the first sample at the maximum setting on the apparatus so as to quickly obtain an approximate idea of the melting point. Once the first sample has melted, allow the instrument to cool ~20°C below the first recorded temperature, and analyze your second sample at a moderate heating rate so as to obtain a more accurate measurement. Points on the report are allocated to how close your measured melting point is to the real value. • DNPH is sold as a moist solid: the solid is only 70% DNPH by mass, with the rest being water. • Be wary of acetone! It can also react under the given experimental conditions: if necessary, it would be wise to rinse your flask with ethanol instead. • After transferring the unknown carbonyl to your reaction flask, rinse the vial with ~1 mL of ethanol to make sure you transfer all of the reagent to the reaction. • Make sure there are no gaps in your reflux apparatus to prevent solvent loss by evaporation. • A Variac setting of ~55% should provide you with a quick yet safe reflux. • Clean a small 50 mL beaker early in the reflux with acetone to make sure it has a chance to dry by the time you need it. • The reaction should boil for at least 5 minutes to ensure a good conversion. • The steps where you have to wait ( e.g. refluxing, cooling, evaporation) are perfect moments to clean dirty glassware or prepare for the upcoming steps. • The solubilities of the crude hydrazone in the 3:1 EtOH/acetone mixture range from ~15–60 mL of hot sol- vent mixture per gram of crude product. • Avoid comparing yourself to your neighbours: each team around you will have a different carbonyl, and each will behave slightly differently throughout the experiment. 7. Weigh a clean and dry 50 mL beaker. Transfer your solid therein, and place it in an oven maintained around 70°C for 10 minutes to finish the drying. Allow the beaker to cool, then weigh it again to obtain the mass of your product.

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