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CHEM 246 Fundamentals of Organic Chemistry Laboratory Nucleophilic Substitution Reactions Page 1 of 13 Nucleophilic Substitution Reactions References: J Chem Ed , 2004 , 81 , 58, and references therein; J Chem Ed , 2006 , 83 , 1344, and references therein. INTRODUCTION: Substitution reactions are used to exchange (substitute) one group on a compound for another. This is one of many methods that chemists utilize for the preparation of complex molecules from simple precursors. Most substitution reactions in organic synthesis are replacing one electronegative group with another electronegative group, where the bonded carbon is partially positive in either case. When these groups have extra electrons to form the new covalent bond, they are called nucleophiles (“Nucleus-loving”). Conversely, when they are the group leaving and taking the electrons from the carbon bond with them, they are called the Leaving Group (LG). Substitution reactions with Nucleophiles (S N ) can proceed in two ways: bimolecular (S N 2) when the slowest step involves the two reactants/compounds coming together at the same time to react, or unimolecular (S N 1) when the slowest step involves only a single compound. An example of an S N 2 (bimolecular) reaction is shown below. R L.G. H H Nu R Nuc H H L.G. Nu = nucleophile L.G. = leaving group A good leaving group is required in both S N 2 and S N 1 reactions. Good leaving groups are anions or neutral groups that are stable in solution after they detach, such as halides (Cl − , Br − or I − ) or weak bases; note that compounds with carbon-halogen bonds are called alkyl halides. S N 2 reactions also require strong nucleophiles (strong as in “reactive”) to remove the leaving group. As the reaction occurs in a concerted manner (the entire reaction takes place in one step), the rate of the reaction depends upon the concentration of both the nucleophile and the alkyl halide. Because the nucleophile attacks in the rate-determining step, the alkyl halide cannot be sterically hindered for the reaction to proceed as this would block the nucleophile’s access to the compound’s reactive site. Therefore, S N 2 reactions are much discouraged on tertiary alkyl halides. S N 2 reactions proceed with inversion of stereochemistry ( R/S ) because the nucleophile approaches from the side opposite the leaving group (shown above).

CHEM 246 Fundamentals of Organic Chemistry Laboratory Nucleophilic Substitution Reactions Page 2 of 13 Alkyl halides can undergo S N 1 reactions as well. An example of an S N 1 reaction is shown below. Because S N 1 reactions involve the formation of a carbocation (a strong electrophile ), weaker nucleophiles can be used. In order to stabilize the carbocation intermediate, making the reaction faster, a more substituted alkyl halide is required (R groups are mildly electron-donating). Since the formation of the carbocation intermediate is the rate-determining step, only the concentration of the alkyl halide affects the rate. Likewise, the sterics of the starting material are not as important as S N 2 because the leaving group departs first, making room for the nucleophile. As a consequence of the intermediate having planar geometry, there is no control over the stereochemistry of the product. In this lab, you will conduct a series of small-scale experiments and observe how the structure of the alkyl halide, identity of the leaving group, and concentration of the reagents affect S N 2 and S N 1 reactions. ASSIGNMENT 1: Watch the video, Nucleophilic Substitutions - S N 1 & S N 2 Comparison (Canvas Module, Start Here page). Use your organic chemistry textbook to revisit the concepts of Nucleophilic Substitution Reactions. PRE-LAB QUESTIONS: 1. Cite two differences between S N 1 and S N 2 reactions. 93± WKGIYOUSY GWK IGWWOKI U[Y OS Y]U YYKUY ]MOQK 93² GWK IGWWOKI U[Y OS USK YYKU³ 93± WKGIYOUSY MG[K G IGWGUIGYOUS OSYKWSKIOGYK ]MOQK 93² IUKY SUY MG[K YMOY YYKU³

CHEM 246 Fundamentals of Organic Chemistry Laboratory Nucleophilic Substitution Reactions Page 3 of 13 2. Show the structure of AgNO 3 . Should nitrate be a good nucleophile or a poor one? Briefly explain your answer. Hint: think about the possible resonance structures. 3. An alkyl halide is reacted with sodium iodide and sodium chloride in separate test tubes. The rate was the same in both experiments. Is this an S N 1 or an S N 2 reaction? Explain. 4. Why is sodium iodide used as a solution in acetone in these experiments instead of a solution in water? =OYM YMOY OSKUWSGYOUS YMK WGYK UK YMK WKGIYOUS YKKSY YU USQ_ IKUKSI US YMK GQQ_Q MGQOIK GSI SUY YMK S[IQKUUMOQK SGQOSM OY GS 93± WKGIYOUS³ /S 93± WKGIYOUSY YMK WGYK IKYKWSOSOSM YYKU OS[UQ[KI OY OS YMK KUWSGYOUS UK YMK IGWGUIGYOUS OSYKWSKIOGYK³ 9OSIK YMK WGYK UK WKGIYOUS OY YMKS OSKQ[KSIKI G_ YMK IUSIKSYWGYOUS UK YMK GQQ_Q MGQOIK GQUSK YMOY OY GS 93± WKGIYOUS³ =GYKW OY G UUQGW YUQ[KSY YMGY IGS KUWS M_IWUMKS GUSIY ]OYM S[IQKUUMOQKY IKIWKGYOSM YMK UKWIKSY _OKQI³ 'IKYUSK MGY SU UWUYUS YU UGWYOIOUGYK OS YMKYK WKGIYOUSY³ YKK GYYGIMKI KOQKY KUW IWG]OSMY

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CHEM 246 Fundamentals of Organic Chemistry Laboratory Nucleophilic Substitution Reactions Page 4 of 13 5. Will the reaction below be an S N 1 or S N 2? Explain briefly, and draw the mechanism in the space below. Cl I 9MOY OY GS 93± WKGIYOUS I[K YU YMK IGWGUIGYOUS OSYKWSKIOGYK IWKGYKI OS YMK SKIMGSOYS³ 9KK GYYGIMKI OSGMK KOQKY KUW IWG]OSMY±

CHEM 246 Fundamentals of Organic Chemistry Laboratory Nucleophilic Substitution Reactions Page 5 of 13 TABLE OF PHYSICAL CONSTANTS AND CHEMICAL HAZARDS: Compound Chemical Structure M.P or B.P 0 C Molecular weight Chemical Hazards Sodium iodide Silver nitrate 1-bromobutane 2-bromobutane 2-bromo-2- methylpropane ( t -butyl bromide) 1-chlorobutane 2-chloro-2- methylpropane ( t -butyl chloride) Ethanol Cite your references for the above information. (Not sure how to properly cite a reference? See the single-page document on “How to cite journals websites and books in your lab report” in Canvas module-2) : ²³´) ´µ¶±·¶ YQOS¸ K_K¸ MGYYWUOSYKYYOSGQ OYY[KY µ´¹±² ´²¶±·º YQOS¸ K_K¸ U[QSUSGW_ OWWOYGYOUS »´´¼±³ ´¹º±½¼ KQGSSGGQK¸ YGSK GY GGU[K YGSK GY GGU[K »´²¶±² ´¹º±½¼ »¼½±½ ´¹º±½¼ YGSK GY GGU[K¸ KQGSSGGQK »´¼¹±´ ¶¼±³º YGSK OWWOYGYOUSY GY GGU[K »¼³±½ ¶¼±³º YGSK GY GGU[K µ²±½²· »´´µ±´ KQGSSGGQK¸ YGSK GY GGU[K 'QQ [GQ[KY YU[WIKI KWUS ]]]±]OQOUKIOG±IUS YKK GYYGIMKI KOQKY KUW GQQ IMKS³ YYW[IY[WKY

CHEM 246 Fundamentals of Organic Chemistry Laboratory Nucleophilic Substitution Reactions Page 6 of 13 IMPORTANT INSTRUCTIONS: • One half of the class will do S N 2, the other half will do S N 1, and exchange the observations to complete the full lab report. Your TA will tell you which set of reactions to do. However, be prepared to do either one of them. • A station is set up in the lab for each reaction. You will only need disposable test tubes, a test tube rack, and disposable Pasteur pipettes (provided in the supply shelves and under-hood cabinets in the lab) to conduct each experiment at the station set up for it. • Please do not move chemicals around or move them away from their respective stations. Also, given their volatile nature, cap the bottles immediately after taking what you need. S N 2 Reactions Experimental Procedure: ASSIGNMENT 2: Watch the Nucleophilic Substitutions - S N 2 video for the general theory, and then Nu Substitution Reactions in the Lab video for a demo of the lab procedure (Canvas Module, Start Here page). To test the properties of S N 2 reactions, we can react a variety of alkyl halides with a solution of sodium iodide in acetone. I - is your nucleophile, and while sodium iodide is soluble in acetone, neither sodium chloride nor sodium bromide is soluble in acetone. Therefore, as the reaction progresses, we will be able to see the formation of a precipitate (see the example below). As shown above, when NaI reacts with the alkyl bromide, NaBr appears as a light yellowish tone in the solution first, which deepens and settles into a pale-yellow precipitate.

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CHEM 246 Fundamentals of Organic Chemistry Laboratory Nucleophilic Substitution Reactions Page 7 of 13 EFFECT OF ALKYL HALIDE STRUCTURE 1. Label three test tubes as 1 , 2 , and 3 . To each of these, add 2.0 mL of 15% NaI in acetone. 2. Add two drops of 1-bromobutane to tube 1 and mix well. Note the time. 3. Add two drops of 2-bromobutane to tube 2 and mix well. Note the time. 4. Add two drops of 2-bromo-2-methylpropane ( t -butyl bromide) to tube 3 and mix well. Note the time. 5. Observe the reactions closely for 15-20 minutes, recording your observations. After 15 minutes have passed, check the reactions every few minutes for the remainder of the lab. Remember that the formation of a precipitate or the appearance of cloudiness in the test tube indicates that the reaction has begun. It is “done” when no more visible precipitate forms. Test tube Chemical structure of the Alkyl halide Nucleophile Reaction time Does it agree with the theory? Explain briefly 1 2 3 EFFECT OF THE LEAVING GROUP 1. Label two test tubes as 4 and 5 . Add 1.0 mL of 15% NaI in acetone to each of the test tubes. 2. Add 2 drops of 1-bromobutane to tube 4 and 2 drops of 1-chlorobutane to tube 5 . Mix them well and record your observations. Test tube Chemical structure of the Alkyl halide Nucleophile Leaving group Any reaction? (Y/N) If Yes, reaction time? Does it agree with the theory? Explain briefly 4 5 ± YKI ±² YKI ´µ YKI _KY¶ UWOSGW_ 93² WKGIYOUSY GWK KGYYKYY I[K YU QGIQ UK GQQ_Q MWU[U MOSIKWGSIK _KY¶ YKIUSIGW_ MGQUGQQGSKY GWK YQU]KW YMGS UWOSGW_ _KY¶ YKWYOGW_ MGQUGQQGSKY MG[K IWU]IKI GQQ_Q MWU[UY YQU]OSM IU]S YMK S[IQKUUMOQK GSI 7] 9KK GYYGIMKI KOQKY KUW GUYM IUQ[SSY YKK GYYGIMKI KOQKY KUW YMKYK µ IUQ[SSY _KY¶ µSOSY SU¶ ?KY¶ 'W OY G GKYYKW QKG[OSM MWU[U _KY¶ )Q OY G UUUWKW QKG[OSM MWU[U

CHEM 246 Fundamentals of Organic Chemistry Laboratory Nucleophilic Substitution Reactions Page 8 of 13 DETERMINATION OF THE RATE LAW 6. Label four test tubes as 6 , 7 , 8 , and 9 . 7. Add 1.0 mL of 15% NaI in acetone to the tubes marked 6 and 7 . 8. To test tube 6 , add 0.1 mL of 1.0 M 1-bromobutane. Write down the starting time. 9. To test tube 7 , add 0.1 mL of 2.0 M 1-bromobutane. Write down the starting time and observe the reaction in tubes 6 and 7 carefully, noting the time, to see evidence of a reaction. 10. Add 1.0 mL of 1.0 M 1-bromobutane to test tubes 8 and 9 . 11. To test tube 8 , add 0.1 mL of 7.5% NaI in acetone. Write down the starting time. 12. To test tube 9 , add 0.1 mL of 15% NaI in acetone. Write down the starting time and observe the reaction in tubes 8 and 9 carefully, noting the time, to see evidence of a reaction. Test tube Alkyl halide structure and its concentration Nucleophile Reaction time Does it agree with the theory? Explain briefly 6 7 8 9 WASTE DISPOSAL: Empty the contents (liquid) in the disposable test tubes into the “HALOGENATED WASTE” bottle. Then, rinse the disposable test tubes and Pasteur pipettes once with the distilled water wash bottle (not acetone) and discard the liquid into the “HALOGENATED WASTE” bottle. Dispose of the rinsed and drained test tubes and Pasteur pipettes in the bucket provided in the chemical hood. YKK GYYGIMKI KOQKY KUW YMKYK ² IUQ[SSY ·¸ YKI ¹ YKI ²· YKI ²º YKI _KY¶ QKYY Y[GYYWGYK SKGS YQU]KW 7] ?KY¶ SUWK Y[GYYWGYK SKGSY KGYYKW 7] )GSSUY IKYKWSOSK KWUS IGYG IGSSUY IKYKWSOSK KWUS IGYG

CHEM 246 Fundamentals of Organic Chemistry Laboratory Nucleophilic Substitution Reactions Page 9 of 13 S N 1 Reactions Experimental Procedure: ASSIGNMENT 3: Watch the video Nucleophilic Substitutions - S N 1 for the general theory and then “ Nu Substitution Reactions in the Lab ” video for a demo of the lab procedure. To test the properties of S N 1 reactions, we can react a variety of alkyl halides with ethanol using a solution of silver nitrate in ethanol. The silver cation will form an insoluble ionic solid with the halide leaving group. Therefore, as the reaction progresses, we will be able to see the formation of a precipitate to indirectly monitor the reaction (see the example below). As shown above, upon reaction with ethanol in the presence of AgNO 3 , 2-bromo-2- methylpropane creates a yellowish, creamy precipitate haze in the solution instantly ( right ). 2- bromobutane creates a hazy grey solution with AgNO 3 ( middle ), while 1-bromobutane creates a mild grey haze ( left ). Indicating differences in the rate of product formation.

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CHEM 246 Fundamentals of Organic Chemistry Laboratory Nucleophilic Substitution Reactions Page 10 of 13 EFFECT OF ALKYL HALIDE STRUCTURE 1. Label three test tubes as 1 , 2 , and 3 . Into each of the test tubes, add 2.0 mL of 0.1 M AgNO 3 solution in ethanol. 2. To test tube 1 , add one drop of 1-bromobutane and mix well. Note the time. 3. To test tube 2 , add one drop of 2-bromobutane and mix well. Note the time. 4. To test tube 3 , add one drop of 2-bromo-2-methylpropane ( t -butyl bromide) and mix well. Note the time. 5. Observe the reactions closely, recording your observations. Remember that the formation of a precipitate or the appearance of cloudiness in the test tube indicates that the reaction has begun. It is “done” when no more visible precipitate forms. Test tube Chemical structure of the Alkyl halide Nucleophile Reaction time Does it agree with the theory? Explain briefly 1 2 3 EFFECT OF THE LEAVING GROUP 1. Label two test tubes as 4 and 5 . Add 2.0 mL of 0.1 M AgNO 3 in ethanol to each of the test tubes. 2. Add 1 drop of 2-bromo-2-methylpropane to tube 4 and 1 drop of 2-chloro-2-methylpropane ( t -butyl chloride) to tube 5 . Mix them well and record your observations. Test tube Chemical structure of the Alkyl halide Nucleophile Leaving group Any reaction? (Y/N) If Yes, reaction time? Does it agree with the theory? Explain briefly 4 5 SW µ¹ ´¼ _KY¸ ²Y SU _KY¶ UWOSGW_ MGQOIKY IU SUY UKWKUWS 93± _KY¶ YKIUSIGW_ MGQOIKY UKWKUWS 93± YQU]KW YMGS YKWYOGW_ ?KY¶ YKWYOGW_ MGQOIKY UKWKUWS 93± YMK KGYYKYY 9KK GYYGIMKI KOQKY KUW YMKYK ² IUQ[SSY 9KK GYYGIMKI KOQKY KUW YMKYK µ IUQ[SSY _KY¶ 'W OY G GKYYKW QKG[OSM MWU[U _KY¶ )Q OY G GGI QKG[OSM MWU[U

CHEM 246 Fundamentals of Organic Chemistry Laboratory Nucleophilic Substitution Reactions Page 11 of 13 DETERMINATION OF THE RATE LAW 1. Label four test tubes as 6 , 7 , 8 , and 9 . 2. To test tubes 6 and 7 , add 1.0 mL of 0.1 M AgNO 3 in ethanol. 3. To test tube 6 , add 0.5 mL of 0.1 M 2-chloro-2-methylpropane in ethanol. To test tube 7 , add 0.5 mL of 0.2 M 2-chloro-2-methylpropane in ethanol. Write down the starting times and observe the reactions carefully, noting the time when you begin to see the precipitate. 4. To test tube 8 , add 1.0 mL of 0.1 M AgNO 3 in ethanol. 5. To test tube 9 , add 0.5 mL of 0.1 M AgNO 3 in ethanol and 0.5 mL of ethanol (this dilutes the silver nitrate). 6. To test tubes 8 and 9 , add 1.0 mL of 0.1 M 2-chloro-2-methylpropane in ethanol. Write down the starting time and observe the reactions carefully, noting the time when you begin to see evidence of a reaction. Test tube Alkyl halide structure and its concentration Nucleophile Reaction time Does it agree with the theory? Explain briefly 6 7 8 9 WASTE DISPOSAL: Empty the contents (liquid) in the disposable test tubes into the “HALOGENATED WASTE” bottle. Then, rinse the disposable test tubes and Pasteur pipettes once with the distilled water wash bottle (not acetone) and discard the liquid into the “HALOGENATED WASTE” bottle. Dispose of the rinsed and drained test tubes and Pasteur pipettes in the bucket provided in the chemical hood. ³·Y ¶Y ¼³Y ¼ºY 9KK GYYGIMKI KOQKY KUW YMKYK ² IUQ[SSY _KY¶ QKYY Y[GYYWGYK ]OQQ IG[YK G YQU]KW WKGIYOUS³ WGYK IKYKWSOSKI G_ GSU[SY UK MGQOIK _KY¶ YMK WGYK OY IOWKIYQ_ UWUUUWYOUSGQ _KY¶ USQ_ IKUKSIY US IUSIKSYWGYOUS MGQOIK _KY¶ USQ_ IKUKSIY US IUSIKSYWGYOUS UK MGQOIK

CHEM 246 Fundamentals of Organic Chemistry Laboratory Nucleophilic Substitution Reactions Page 12 of 13 ANALYSIS: a. Compare your results/observations with the theory and explain the effect of alkyl halide structure on S N 1 & S N 2 reactions. b. Compare your results/observations with the theory and explain the effect of the leaving group on S N 1 & S N 2 reactions. c. Comparing your results/observations with the theory, what can you say about the rate laws of S N 1 reactions and S N 2 reactions? Explain briefly. 9MK WKY[QYY ]KWK GII[WGYK YU YMK YMKUWOKY YMGY Y[UUUWY 93± » 93² WKGIYOUSY³ /S U[W 93± WKGIYOUSY YMK UWOSGW_ MGQOIK IOI SUY WKGIY¶ ]MOQK YMK YKIUSIGW_ GSI YKWYOGW_ IOI WKGIY W[OIQQ_³ /S U[W 93² IGYG¶ YMK UWOSGW_ MGQOIK WKGIYKI YMK KGYYKYY I[K YU QGIQ UK YYKWOI MOSIWGSIK³ 9MK YKIUSIGW_ GSI YKWYOGW_ UWUIKKIKI OS YU YMK YQU]KYY GKOSM YMK SUYY YYKWOIGQQ_ MOSIKWKI ¼YMK YKWYOGW_½³ +UW 93± WKGIYOUSY MUUI QKG[OSM MWU[UY GWK ]KGQ GGYKY ]MOIM IGS YYGGOQO_K YMK SKMGYO[K IMGWMK YMK_ GIW[OWK³ 93² WKGIYOUSY WKW[OWK YYWUSM S[IQKUUMOQKY GSI QKG[OSM MWU[UY OS YMKOW WGYK IKYKWSOSGYOUS³ 9MK QKG[OSM MWU[U YMU[QI GK MUUI G[Y SUY K[QQ_ YYGGQK QOQK GS OUS³ /S 93± WKGIYOUSY YMK WGYK OS U[W IGYG ]GY IKYKWSOSKI G_ YMK IUSIKSYWGYOUS GSI IMKSOIGQ YYW[IY[WK UK YMK MGQOIKY³ 3KGS]MOQK¶ 93² WKGIYOUSY GWK OSKQ[KSIKI G_ GUYM YMK MGQOIK GSI YMK S[IQKUUMOQK³

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CHEM 246 Fundamentals of Organic Chemistry Laboratory Nucleophilic Substitution Reactions Page 13 of 13 POST-LAB QUESTIONS: 1. Which would react faster with sodium iodide, (a) 1-fluorobutane or (b) 1-bromobutane? Explain why. 2. Would the reactions you tested using sodium iodide have worked if you had used alcohols as the starting materials in place of alkyl halides? Why or why not? 3. Would the reactions you tested using silver nitrate in ethanol have given the same observations if you had used sodium nitrate in ethanol instead? What, if anything , would be the difference? 9OSIK YMK YYWKSMYM UK MGQUMKS GUSIY IKIWKGYK GY _U[ SU[K IU]S YMK MWU[U¶ ±¾GWUSUG[YGSK ]U[QI GK KGYYKW I[K YU OYY MOMMKW WKGIYO[OY_³ 'WUSOIK OY G GKYYKW QKG[OSM MWU[U GQQU]OSM OY YU GK IOYUQGIKI G_ YUIO[S OUIOIK³ 9MK 5- MWU[U OS GQIUMUQ OY SUY G MWKGY QKG[OSM MWU[U¶ GSI SKKIY YU GK GIYO[GYKI G_ GIIOSM KOYMKW GS GIOI UW -¿ OS UWIKW KUW YMOY WKGIYOUS YU YGQK UQGIK³ 5WUYOI YUQ[KSYY GWK [YKI OS 93± WKGIYOUSY OS UWIKW YU MKQU OS YMK IOYYUIOGYOUS UK YMK MGQUMKS YYGGOQO_GYOUS UK WKY[QYOSM OUSY³ /K 'M35µ OY WKUQGIKI KOYM 3G5µ YMK YGSK WKY[QY ]U[QI UII[W³