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Substitution Reaction Experiments of AlcoholContaining Compounds Jaylee Miller (reaction scheme 1), Taylor Targgart (reaction scheme 3) Department of Chemistry and Chemical Biology, IUPUI, 402 N. Blackford St., Indianapolis, IN 46202 [email protected]

The purpose of this experiment was to obtain a specific product through the use of materials such as starting materials, reagents, and solvents. The specific reactions being tested follow a substitution mechanism such as SN1 and SN2 which the identity depends upon certain characteristics. Reaction Scheme 1, which is the reaction of 3-phenyl-1-propanol with sodium bromide and sulfuric acid, has characteristics that favor SN2. These characteristics are that the hydroxyl substituent is primary and there is a strong nucleophile, which is sodium bromide. This reaction overall will produce (3bromopropyl)benzene. Reaction Scheme 3, which is the reaction of 2,4-dimethyl-3-pentanol with hydrochloric acid and zinc chloride, has characteristics that favor SN1. These characteristics are having a secondary substituent group and its reaction with hydrochloric acid which is a weak nucleophile. The minor product that is produced is 3-chloro2,4-dimethylpentane which has a secondary alkyl halide. The major product that is produced is 2-chloro-2,4dimethylpentane which has a tertiary alkyl halide. This major product is produced due to a hydride shift during rearrangement. Substitution reactions are a very important mechanism in understanding exactly how reactions work and the resulting products. These types of reactions also have a few vital roles in everyday life that are important to discuss such as medicine that is more directly related to instances in pharmacology and chemotherapy. For substitution reactions, there are two types: SN1 and SN2. Different characteristics can be applied to both reactions to differentiate them from each other as well as show some similarities. All substitution reactions contain a leaving group along with a nucleophile, but the type of nucleophile is what differentiates them. Important characteristics include the strength of the nucleophile, type of solvent, structure, and number of steps present. SN1 is considered unimolecular and has a step-wise manner. The rate of the reaction solely

depends upon the concentration of the substrate, not the nucleophile. The first step of this reaction is the loss of a leaving group, which is the rate determining step unless there is a hydroxyl present which must first be protonated to leave. The solvent present, which must be polar protic, will act as the proton source for this. Once there is a loss of the leaving group, a carbocation intermediate is formed. This step can lead to multiple products being formed if there are rearrangements that can occur such as hydride shifts to make the intermediate more stable. Another characteristic of the SN1 pathway is that it favors a tertiary carbocation over primary and secondary options. The next step is for the nucleophile to attack the location of the carbocation. It is important to note that although a strong nucleophile is favored, SN1 reactions can still react with a weaker nucleophile. The differences between SN1 and SN2 are the key to understanding what each means, therefore for SN2 it is important to note that it is concerted and considered bimolecular. This reaction’s rate depends upon the substrate and the nucleophile. Simultaneously, the leaving group leaves while the nucleophile attacks. This reaction is also the same in that if there is a bad leaving group present, it must first be protonated before leaving. The nucleophile must be strong for this reaction to occur. Since this reaction is concerted, there are no carbocation intermediates that are formed, which is also true due to the fact that the nucleophile can only attack on the opposite side of the leaving group. Since the reaction partakes in inversion of configuration, it is best suited for a primary substrate over a secondary or tertiary substrate. The best solvent for an SN2 reaction is a polar aprotic solvent since there is a lack of hydrogen, which means they can only stabilize the cation of the nucleophile. These two types of substitution reactions create different products from each other, and sometimes even multiple products which can be seen in both Scheme 1 and Scheme 3 that will be discussed. Methods for analysis of these products created can be done through techniques such as IR spectroscopy, 1H NMR, TLC, and GC. IR spectroscopy is used to analyze what functional groups are present on a sample being tested, but in this specific experiment, substituent groups are being tested to see if the sample is similar to the hypothetical product given. 1H NMR is used to analyze what the structure of the sample being tested is. Gas chromatography (GC) can be used for separating/analyzing compounds, specifically to test for purity of the sample. For this specific experiment, gas chromatography is able to test for the percentage of a product being made, thus showing the minor and major product being produced by a SN1 reaction. Thin layer chromatography (TLC) can be used to separate the compounds so that they can be analyzed, which, in this specific case, is to make sure that a product was formed by comparing polarities. These methods can be used to analyze the reactions as well as show if the reaction underwent a SN1 or SN2 reaction. A very important process used for the synthesis of these reactions is heating under reflux, which is when a solution is heated while attached to a condenser to prevent the reagents being used from escaping. This process is extremely important because it not only accelerates the reaction process but also helps to prevent the product from being lost which ensures a better percent yield when done correctly.

Scheme 1. Substitution of 3-phenyl-1-propanol to form (3bromopropyl)benzene

The reaction scheme for 3-phenyl-1-propanol proceeds through a SN2 path due to a strong nucleophile being present and having a primary substituent that leads to a concerted mechanism. Sodium bromide acts as a strong nucleophile and a weak base, which leads to the production of (3bromopropyl)benzene. Sulfuric acid is the solvent in this mechanism and acts as a catalyst, as well as protonating the hydroxyl group at the beginning of the reaction. Once the leaving group leaves, the bromine attacks all in one step. To confirm that the reaction went through SN2, the product was run through IR and H NMR. The first peak observed in the IR data was at 3413, which represents a small OH peak. Another peak observed was at 1340, which indicates an aromatic that is present cm . A peak was then seen at 744 cm , which indicates an aromatic substitution that is present. 1H NMR indicated a signal around 7.25 ppm which represents an aromatic ring with a substituent. The splitting of this signal is 5H and multiplet. Another signal that is considered significant is seen at 3.4 ppm, which indicates a CH group adjacent to a CH group and a bromine. This peak has a splitting of 2H and triplet. Another analyzation technique that was used was TLC, which can confirm the presence of the product that was formed versus the starting material. This technique helps due to the polar silica gel that the TLC plate is covered with. Two R values were provided form TLC, the first value was 0.3 which indicated 3-phenyl-1-propanol and the second value was 0.6 which indicated (3-bromopropyl)benzene. 3-phenyl-1propanol has a hydroxyl group which causes it to be more polar than the product due to hydrogen bonding. Since it is more polar, it travels a less distance on the TLC plate than the reactant, (3-bromopropyl)benzene, did. Through the three techniques of analysis discussed, each supported either the structure of the product or the polarity comparison. One last numerical data to discuss is the percent yield. For the reactant, 3.00 grams were used in the reaction, which produced 1.49 grams of product while the theoretical yield was calculated as 4.386. This resulted in a percent yield of 33.97%. 1

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Scheme 3. Substitution of 2,4-dimethyl-3-pentanol to form 3chloro-2,4-dimethylpentane and 2-chloro-2,4-dimethylpentane

The reaction scheme for 2,4-dimethyl-3-pentanol has a SN1 pathway due to the characteristics the reaction has present. These characteristics include a secondary substrate and a weak nucleophile. Since this reaction is step-wise, there are two products that form, the major product being 2-chloro-2,4dimethylpentane and the minor product being 3-chloro-

2,4dimethylpentane. This reaction starts with the hydroxyl group being protonated so that it is a good leaving group and is thus removed which creates a carbocation. For the major product, a hydride shift will then occur to create a more stable carbocation, while the minor product does not partake in this rearrangement. The nucleophile, hydrochloric acid, will then attack the carbocation in each of these instances. The product produced was analyzed using IR, GC, and 1H NMR to ultimately test the purity of the product. The first significant peak seen in IR was at 2964 cm , which indicated sp3 C-H bonding. Another significant peak was at 1455 cm , which indicated C-H bonding. Lastly, a significant peak was seen at 439 cm , which indicated C-Cl bonding. Analyzation of 1H NMR showed a significant signal at 2.49 ppm with 1H splitting which indicates a C-Cl group. Another important signal that was seen is at 1.7 ppm with splitting of 6H and indicates a saturated alkene. Lastly, an important signal was seen at 1.95 with 8H splitting that indicates another saturated alkene. The results of GC concluded two peaks, which proves that a major and minor product were produced. The first peak consisted of 13.5% of the sample, which indicates the minor product that is 3-chlor0-2,4-dimethylpentane. The second peak consisted of 86.5% of the sample, which indicates the major product that is 2-chloro-2,4-dimethylpentane. Through the use of IR, 1H NMR, and GC the identity of the product was concluded to be both 3-chloro-2,4dimethylpentane and 2-chloro-2,4-dimethylpentane. through analysis of the IR, GC, and H NMR data. The products also showed that there were similarities to an SN1 reaction. For the reactant, 3.00 grams were used in the reaction, which produced 1.27 grams of product while the theoretical yield was calculated as 3.48. This resulted in a percent yield of 36.5%. -1

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Experimental Section All reactions that were carried out were under normal atmospheric conditions. Chemicals were used from the manufacturer’s bottle unless stated otherwise. 1H NMR spectra were gathered using Bruker Top Spin 400 MHz spectrometer. IR spectra were gathered using a ThermoNicolet 380 FT-IR. Gas chromatographs were obtained using a GOW-MAC 69-400-TCD GC. (3-bromopropyl)benzene. (1). In a round bottom flask (100 mL) add 3-phenyl-1-propanol (3 g), sodium bromide (2.39 g), sulfuric acid (3 mL, 9M), and a spin bar. Reflux for ~30 minutes with a thermowell, gently increasing the temperature. The reaction is complete when a red layer on the bottom forms (NaBr) and there is an organic layer present on top. Let the reaction cool to room temperature. When transferring to a separatory funnel, make sure to get only the organic layer, avoiding the solid. Wash with 5% NaHCO3 2 X 6 mL. This wash turns leftover acid into salt that dissolves into the aqueous layer. Dry the final product with sodium sulfate. Run an IR, TLC Plate, and H NMR to check the purity and see if the product was made, making sure to not pick up any of the sodium sulfate. 3-Phenyl-1-Bromopropane. 1H NMR (CDCl3, 400 MHz): δ 7.25 (m, 5H), 3.65 (t, 1H), 3.4 (t, 2H), 1

3.7 (m, 2H), 2.15 (m, 2H). IR (cm-1): 3413, 2939, 1270, 744. Rf values: 0.6 (3-bromopropyl)benzene, 0.3 3-phenyl-1propanol. 3-chloro-2,4-dimethylpentane. (3). In a round bottom flask (100 mL) add 2,4-dimethyl-3pentanol (3.6 mL) and Lucas reagent (4 mL). Reflux for ~30 minutes with a thermowell, at a steady temperature. The reaction is complete when there are two distinct layers, a clear layer and an oil colored layer. Let the reaction cool to room temperature, then transfer to a separatory funnel. Wash with two equivalents of diH O (5 mL) and two equivalents of 5% NaHCO (5 mL), keeping the top layer of each wash. The final product will be the top layer after the final wash. Dry the final product with sodium sulfate. Run an IR, GC, and H NMR to check the purity and see if the product was made. 3-chloro-2,4-dimethylpentane (minor product) and 2-chloro-2,4-dimethyl pentane (major product). IR (cm ) 2964, 1455, 439. GC (TCD) [of mixture] 7.50 m (13.5%), 10.50 m (86.5%). H NMR (CDCl3, 400 MHz): δ 2.49 (s, 0.45H), 1.7 (m, 6.00H), 1.95 (m, 7.54H). 2

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Conclusion The purpose of this experiment was to show how specific starting materials react with reagents and solvents to produce a hypothetical product through nucleophilic substitution. Reaction 1 contains a primary substrate and a strong nucleophile, which corresponds to a pathway of S 2. During this pathway, a carbocation intermediate is not formed. This reaction is supported through the numerical data provided with H NMR, IR, and TLC. Reaction 3 has a secondary substrate which results in a S 1 pathway. A carbocation intermediate is formed, which causes a hydride shift that results in two products. This reaction was supported by the values that H NMR, IR, and GC provided. Errors that occurred that could further increase the purity of products for Reaction 1 and 3 includes improper separatory techniques, the under drying of product, and reflux time. To improve these errors, it is important to mix properly in the separatory funnel by tilting back and forth along with carefully separating the contents when emptying it. To fix the error of under drying, sodium sulfate should be added until it stops clumping, which should result in a smaller OH peak. Lastly, reflux has to be carried out carefully by increasing the temperature slowly and stopping the process when the two distinct layers have formed so that reflux is completed. Fixing the separatory technique and reflux may result in a higher percent yield and purity of the products. Overall, the purpose of this experiment was a success in showing how specific organic reactions are performed under a set of conditions to obtain the desired product. N

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Acknowledgement. This work was made possible by the Department of Chemistry and Chemical Biology at IUPUI. References. 1.

Denton, R.E.; Audu, C. “Investigating Substitution Reactions of Various Alcoholic Compounds.” Fake Journal of Organic Chemistry 2010, 77, 3452-3453.

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Klein, David R. Organic Chemistry. 3rd ed., 2017.

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Patrick, F. Boles, et al. Organic Chemistry I, laboratory manual, 2010....