Experiment 9: Nucleophilic Substitution Reactions of Organic Halides

Introduction: Substitution Reactions Substitution reactions are reactions where the two species involved exchange parts:

Na C + Br C C + NaBr C

There are two types of substitution reactions that commonly occur in organic chemical reactions, the SN1 and the SN2 reactions. They have different mechanisms which means their ability to occur is determined by factors like sterics around the alkyl halide, the choice of nucleophile used or even the solvent for the reaction.

1. SN1 (Substitution, Nucleophilic, Unimolecular)

Pertinent SN1 Facts

The SN1 reaction is called “unimolecular” because the rate of this type of reaction is dependent upon only one species in the rate-determining step, the alkyl halide.

r.d.s. Nuc C X C + X C Nuc (slow) (fast)

The rate of reaction is ONLY dependent on how quickly a carbocation might form by “spontaneous dissociation”. Remember that the nucleophile is NOT involved in this step.

Factors that affect the rate of an SN1 Reaction: 1. The Alkyl Halide must form a stable carbocation, and the more stable the carbocation, the faster it will form, causing the overall reaction to occur quicker (more stable intermediate = lower activation barrier).

Recall that alkyl groups stabilize carbocations through both inductive effect and hyperconjugation.

The order of carbocation stability: 3º > 2º >>>>>> 1º or methyl

Resonance Stabilization adds a tremendous amount of stabilization to a carbocation and can also allow an SN1 reaction to occur faster since resonance also stabilizes carbocations – the more the charge can be spread out over multiple atoms, the more stable the charge will be (“delocalization”). An allylic or Benzylic 1º carbocation is easily as stable as a normal 2º carbocation.

2. Leaving Group: Same order of reactivity seen for SN2 reaction ⊖ ⊖ ⊖ ⊖ Halides: I , Br > Cl , H2O >>> F (best) (worst)

3. The Nucleophile does NOT affect the rate of the reaction because it is not part of the rate-determining step. The nucleophiles in this type of reaction are often weak bases, usually neutral molecules like H2O or ROH. Today we are using ethanol,

CH3CH2OH, as your nucleophile.

4. The choice of solvent affects rate by affecting a reagent’s energy levels. Solvent molecules do what is called “solvation”, meaning they surround certain species in a reaction. The solvent can affect the rate of SN1 reaction by stabilizing the carbocation intermediate as it forms, thus increasing the rate of reaction. Any POLAR solvent can be used to do this. The solvent today is ethanol, CH3CH2OH, and it will act as both the nucleophile AND the solvent (a “solvolysis” reaction).

H CH2CH3 O H H O CH CH H3CH2C O 2 3 O CH CH H3CH2C O 2 3 H O H H CH2CH3

SN1 Reaction Conditions: Each compound will be treated with a solution of silver nitrate in ethanol. Ethanol is a polar, protic solvent that favors ionization of the alkyl halide to form stable carbocations. This is facilitated by the silver ion coordinating to the halide through a lone pair on the halogen atom, causing a weakening of the carbon-halogen bond. Silver halide salts are very insoluble and will precipitate from the solution, indicating if a reaction has occurred. The nitrate ion and ethanol solvent are both poor nucleophiles and so SN2 reactions do not occur. Ag+ R X R X Ag R + AgX(s)

HOCH2CH3

R-OCH CH 2 3

2. The SN2 Reaction (Substitution, Nucleophilic, Bimolecular)

The SN2 type reaction is a one-step, concerted substitution process (make new bonds, break old bonds simultaneously). Both the alkyl halide and the nucleophile are involved (“bimolecular”) to determine the rate of reaction:

2 Nuc X + X

Nuc

Factors that affect the SN2 Reaction: 1. Steric Congestion of Alkyl Halide -The more congested and sterically hindered the alkyl halide, the slower the reaction. Remember that alkyl halides have sp3 hybridized carbons, to which the halide is bonded.

Fastest Slower Never

CH3-X > RCH2-X > R2CH-X >>>>>>>>>>>>>>> R3C-X

2. The Leaving Group is what the halide is referred to in a substitution reaction and it is the group that must leave the alkyl halide. It is almost always expelled with a full negative charge in an SN2 reaction. The best leaving groups will be those that can best stabilize the anion (i.e. the weakest bases).

Halides: I⊖ , Br⊖ > Cl⊖ >>> F⊖ (best) (worst)

3. The choice of solvent affects rate by affecting a reagent’s energy levels. Today you will be using acetone, which is a relatively polar and aprotic solvent. Polar, aprotic solvent molecules solvate the metal counterion of the nucleophile (in today’s lab: Na+ of the I-). This will expose the iodide anion so it will be destabilized and more reactive.

O O O I Na O O exposed!! O

4. Nucleophile – the species that causes a substitution reaction to occur. For atoms in the same family (column) on the periodic table, as they become larger (as you move DOWN a column on the periodic table), they are better nucleophiles. Larger atoms will ⊖ be more polarizable, thus making I an excellent choice for SN2 reactions.

SN2 Reaction Conditions: Each compound will be treated with a solution of sodium iodide (excellent nucleophile) in acetone (polar, aprotic solvent). Also, sodium iodide, NaI, is soluble in acetone whereas sodium bromide and sodium chloride are not. The formation of a precipitate of either NaBr or NaCl will therefore indicate that a reaction has occurred.

3

R Cl + Na+I- acetone R I + NaCl(s)

+ - R Br + Na I R I + NaBr(s) acetone

Introduction: Experiment In this experiment the reactivity of seven different alkyl halides towards nucleophilic substitution reactions will be examined. There are several factors that may influence the reactivity, including the structure of the substrate, the leaving group and the reaction conditions (both solvent and temperature). Here, we will perform two sets of experiments to test the reactivity of each, under conditions that favor SN2 and under conditions that favor SN1. The structures of the substrates are given below.

Br CH CH CH CH Cl CH -CH-CH CH 3 2 2 2 3 2 3 CH3-CH-CH2CH3 Cl Br 1-chlorobutane 2-chlorobutane 2-bromobutane bromobenzene

CH3

CH3-CH-CH2Cl H3C C Cl CH3CH=CHCH2Cl

CH3 CH3 1-chloro-2-methylpropane 2-chloro-2-methylpropane 1-chloro-2-butene (cis/trans mixture)

FOR YOUR SAFETY Wear Gloves - Organic halides are irritants and in certain cases corrosive. Silver salts will stain skin black and this is very hard to remove. Wear gloves and dispense with the syringes that are provided. Procedure

A. Reactivity with AgNO3 in ethanol (SN1) 1. Obtain a thermometer. Add approximately 1 inch depth of hot tap water to a large beaker and place on your hotplate at a setting of 2 to set up a water bath and stabilize the water temperature at 45°C. Clamp a thermometer in the water so that you can monitor the temperature. Make sure the thermometer is not touching the bottom of the beaker (or you’ll be recording the temperature of the glass beaker, not the water!) 2. To your clean test tubes labeled #1-7 (washed from part A), and using the color- coded 1.0 mL syringes provided, add 0.1 mL of an organic halide (in this order, to avoid confusion):

(1) 1-chlorobutane (2) 2-chlorobutane (3) 2-bromobutane 4 (4) bromobenzene (5) 1-chloro-2-methylpropane (6) 2-chloro-2-methylpropane (7) 1-chloro-2-butene Place a cork stopper in each of the tubes and stand the tubes in a test tube rack.

Again, to avoid confusion during Steps 3-6, do not attempt to do all 7 test tubes in a single trial. Perform Steps 3-6 on the first three compounds listed, then repeat Steps 3-6 on the final four compounds.

3. Rapidly transfer 1 mL of a 1% AgNO3 solution in ethanol to each tube and mix thoroughly by swirling. Replace the cork stopper in each tube and start timing.

Note 1: the designated timekeeper should start a running timer (Stopwatch on cell phone!) and make note of the START TIME for each addition to each test tube (i.e. 0:02 min, 0:25 min, 0:50 min, etc).

4. Watch each test tube carefully and note the time at which a precipitate appears (END TIME) and its color. The timekeeper must record the end time from the running stopwatch (1:03 min, 4:15 min, etc).

Note 2: The time for the reaction is the difference between the START and the END (0:02 to 1:03 = 1 min, 1 sec and 0:25 to 4:15 = 3 min, 50 sec. Remember we are using min/sec and there are 60 seconds per min!

5. If after 5 minutes no precipitate is visible, move any test tubes that have no precipitate into the 45°C water bath and continue watching them for the formation of precipitates. 6. Heat for no more than 6 more minutes (11 minutes total), noting the END TIME for any precipitates that form in the hot bath, then remove the tubes from the hot bath and cool to room temperature. 7. When your observations are completed, pour all the solutions into the silver salts waste container, rinse the tubes with ethanol and place those washings in the same container. A 10% thiosulfate solution can be used to remove any residual silver halide precipitates (thiosulfate ion dissolves silver halides) – place these washings in the silver waste container also. Then wash with water and rinse with acetone (dispose of acetone rinses in acetone waste). Unless told otherwise, use the same test tubes for part B below.

5 Review your observations and record the reactivity order for each set of conditions, such as: “1,2 (immediate reaction) > 3 > 4,5 (required heating to react) > 6,7 (did not react)”.

B. Reactivity with NaI in acetone (SN2) 1. Keep the hot water bath from part A and maintain at 45°C. 2. To your clean test tubes labeled #1-7 (washed from part A or a fresh set if provided), and using the color-coded 1.0 mL syringes provided, add 0.1 mL of an organic halide (in this order, to avoid confusion):

(1) 1-chlorobutane (2) 2-chlorobutane (3) 2-bromobutane (4) bromobenzene (5) 1-chloro-2-methylpropane (6) 2-chloro-2-methylpropane (7) 1-chloro-2-butene Place a cork stopper in each of the tubes and stand the tubes in a test tube rack. To avoid confusion during Steps 3-6, do not attempt to do all 7 test tubes all at once. Perform Steps 3-6 on the first three compounds listed, then repeat Steps 3-6 on the final four compounds.

3. Rapidly transfer 1 mL of 18% NaI in acetone solution to each test tube and mix thoroughly by swirling. Replace the cork stopper in each tube and start timing. Note: The designated time keeper should start the timer (cell phone!) and note the start time for each addition to each test tube (i.e. 0:02 min, 0.15 min, 0.35 min, etc) and then record the end time for each as well. 4. Watch each test tube carefully and note the time at which a precipitate appears and its color. 5. After 5 minutes, place any test tubes that have no precipitate into the 45°C water bath. Again, watch for the formation of precipitates. 6. Heat for up to 6 minutes then remove the test tubes and allow to cool to room temperature. As some acetone may have evaporated during heating, there is the possibility of a precipitate of unreacted starting material, NaI, forming on the walls of the test tube. To guard against this “false positive” result, gently shake these tubes for a few minutes which should redissolve any NaI, but leave other precipitates unchanged. Note if precipitate disappeared upon shaking. Record all results. 7. Empty the test tubes into the halide waste container, using a brush to remove traces of solids if necessary. Wash the tubes out thoroughly with water to remove all traces of solids, then with acetone (acetone rinses must go in acetone waste container) and dry them. It is important that there are no traces of iodide 6 ion left for as this would give future false positive results for anyone doing the

SN1 series of reactions in your test tubes.

DATA TABLES – Set up two tables – one for each type of substitution reaction – and record the following information in your notebook:

Reaction: (Insert type) Room Temperature 45ºC Water Bath (if needed) Compound #: Name Timer Timer Precipitate? Timer Timer Precipitate? Start Stop Y/N (color) Start Stop Y/N (color)

1: 1-chlorobutane

2: 2-chlorobutane

3: 2-bromobutane

4: bromobenzene

5: 1-chloro-2-methylpropane

6: 2-chloro-3-methylpropane

7: 1-chloro-2-butene

7