Nucleophilic Substitution - Organic Chemistry - Lecture Notes, Study notes of Organic Chemistry

Download Nucleophilic Substitution - Organic Chemistry - Lecture Notes and more Study notes Organic Chemistry in PDF only on Docsity! 1 Nucleophilic Substitution In this chapter we re-examine nucleophilic substitution reactions in more detail, paying particular attention to stereochemistry and other details of the reaction mechanism. We will look at what makes a good nucleophile and we will examine solvent effects on substitution reactions. We will also see that substitution reactions compete with elimination reactions and we will study the conditions that favor substitution versus elimination and conditions that favor elimination over substitution. With alkyl halides, the R-X bond is partially polarized with the R-group having a partial positive charge and the X group having a partial negative charge. The Y-group is the nucleophile and the R-group, with its partial The X-group is the leaving group and leaves with the two electrons in the R-X bond. The new R-Y bond is formed with the two electrons that come from the nucleophile Y. The nucleophile, by definition, donates two electrons to the electrophile. In order to be a nucleophile, it must have two electrons. In a later section we will discuss what it is that makes a good nucleophile. R X δ+ δ− +Y Y R + X nucleophile electrophile leaving group Examples of common nucleophiles: (1) Alkoxides, RO-, used to make ethers. R O + R' X R O R' + X Ex. CH3CH2 O + CH3 Br CH3CH2 O CH3 + Br ether (2) Carboxylate, RCO2-, used to make carboxylic acid esters. R C O O R' X+ R C O O R' + X Ex. CH3CH2 C O O CH3 Br+ CH3CH2 C O O CH3 + Br ester docsity.com 2 (3) Hydrogen sulfide anion, HS-, used to make thiols. H S + R' X H S R' + X H S H S CH2CH3 + Br thiol CH3CH2 Br (4) Cyanide anion, NC-, used to make alkyl cyanides. N C + R' X N C R' + X Ex. N C + CH3CH2 Br N C CH2CH3 + Br (5) Azides N N N azide anion Na+ CH3CH2CH2 Br N N N CH2CH2CH3 (6) Iodides I Na CH3CH2CH2 Cl CH3CH2CH2 I + NaCl Substitution reactions cannot be done at sp2 carbon centers. C C Cl H H CH3CH2 HO No Reaction Br HO No Reaction There are two main reasons for this. docsity.com 5 CH3CH2 C Br D HHO + HO C Br D CH2CH3H δ−δ− HO C CH2CH3 H D (S)-1-bromo-1-deuteriopropane (R)-1-deutreio-1-propanol Steric Effects SN2 reactions are very sensitive to steric hindrance. Tertiary substrates react very slowly by the SN2 mechanism, if at all. The best substrates are methyl and primary alkyl halides. Secondary substrates will react by the SN2 mechanism but will do so relatively slowly. H C H H X least crowded, most reactive > R C H H X > R C R H X primary secondary R C R R X> tertiary least reactive by SN2 most crowded The nucleophile must approach the electrophilic carbon from the backside. With tertiary substrates this approach is very crowded and the reaction is very slow. C C C C Br H H H HH H H H H HO The backside approach is very hindered in tertiary substrates. And neopentyl bromide also reacts very slowly, even though it is a primary alkyl halide, partially blocked by the methyl groups on C2. Neopentyl bromide reacts about 10-5 times more slowly than ethyl bromide. CH3 C CH3 CH3 CH2 Br NaOH CH3 C CH3 CH3 CH2 OH CH3CH2 Br NaOH CH3CH2 OH relative rate = 1 relative rate = 10-5 Nucleophilicity docsity.com 6 We will now look at what makes a good nucleophile. By definition a nucleophile is a species that donates electrons to the electrophile. To be a nucleophile, a species must have at least a lone pair of electrons that it can donate. It does not have to be an anion. For example, all of the following are good nucleophiles: amines R1 N R2 R3 phosphines R1 P R2 R3 R1 S R2 sulfides R1 S H thiols R1 O H alcohols Solvolysis reactions are those in which the solvent is also the nucleophile. These are common in water and alcohol solvents. RX + 2 H2O ROH + H3O+ X- For example, a hydrolysis reaction in water: H O H + CH3CH2 Br slow O CH2CH3 H H + Br- O CH2CH3 H H H O H + H O H H + H O CH2CH3 step 1 step 2 A methanolysis reaction in methanol: CH3 O H + CH3CH2 Br slow O CH2CH3 CH3 H + Br- O CH2CH3 H H CH3 O H + CH3 O H H + CH3 O CH2CH3 step 1 step 2 Nucleophilicity is a measure of the strength of the nucleophile. We do not have an exact scale that measures the strength of a nucleophile the way we do for measuring the strength of acids using the pKa scale but we can make some generalizations. docsity.com 7 General Rules for Predicting the Strength of a nucleophile: (1) If the attacking atom in two nucleophiles is the same in each and one of them has a charge, the nucleophile with the charge will be the stronger nucleophile. RO > ROH > RSHRS R C O O > R C O OH (2) If the attacking atom in two nucleophiles is the same, the more basic the atom, the better the nucleophile. RO > R C O O pKa ROH = 16 pKa R C O OH = 5 This is also true for atoms in the same row: the stronger the base, the better the nucleophile. HO > F This is true only for atoms in the same row. It is not true when going down a column. For example, among the halogens, iodide is the best nucleophile and fluorine is the worst. I > Br > Cl > F best nucleophile worst nucleophile This trend is also true for other columns. For example, HS- is a better nucleophile than HO-. Probably the main reason for this has to do with solvation. For reactions in solution the small, highly electronegative fluorine anion is tightly surrounded by solvent molecules and so is less available to react as a nucleophile. Its electrons are not free to react because they are partially bound to the solvent molecules surrounding them. In the gas phase, where there is no solvent, the reactivity order is exactly the opposite: F- > Cl- > Br- > I-. docsity.com 10 Transition state 1 CH3 C CH3 CH3 Br δ−δ+ The second and third transition states both resemble the starting materials since these reactions are fast, and exothermic. CH3 C CH3 CH3 O H H δ+ δ+Transition state 2 exothermic reaction, early transition state, little build up of charge Transition State 3 CH3 C CH3 CH3 O H O H H H exothermic reaction, early transition state, little build up of charge The reaction rates for SN1 reactions are determined by the rate of formation of the carbocation. As we have learned, the more stable carbocation forms fastest because it is lower in energy. Therefore tertiary substrates, which form tertiary carbocations in the first step, react the fastest by the SN1 mechanism. This is very rapid at room temperature. Reactivity order for alkyl substrates: R3CX tertiary reacts fastest, forms most stable carbocation > R2CHX > RCH2X > CH3X secondary primary methyl The reactivity order for SN2 reactions is exactly the opposite: CH3X methyl > RCH2X > R2CHX > R3CX primary secondary tertiary least hindered most hindered In general: Methyl and primary alkyl halides never react by SN1 mechanisms, always by SN2. Tertiary alkyl halides never react by SN2 mechanisms, always by SN1. Secondary alkyl halides can give a mixture of SN1 and SN2 but it depends to a large extent on the nucleophile: docsity.com 11 - Good nucleophiles tend to give mainly SN2. - Poor/weak nucleophiles tend to give mainly SN1 (as in solvolysis reactions). Stereochemistry of SN1 Reactions Usually we see at least some racemization of chiral substrates in SN1 conditions but we usually do not get an exactly 50:50 mixture of the two isomers. Generally, the leaving group partially shields one side of the carbocation so that there is a slight predominance of attack of the nucleophile from the side away from the leaving group. C CH2 Br CH3 CH3CH2 NaI C CH CH3CH3CH2 Br CH2 CH3 CH2 CH3 I I Approach is partially blocked by the leaving Br-, so more product results from attack opposite the Br-. I C CH2 CH3 CH2CH3 CH2 CH3 > 50% C CH2 CH2 CH3 ICH3 CH3CH2+ < 50% Rearrangements Since there is a carbocation intermediate, rearrangements will occur. For example, in the following solvolysis reaction, most of the product results from the rearrangement of the secondary carbocation to the tertiary carbocation by means of a hydride shift in this case. This step is very fast since a higher energy species is being converted to a lower energy species. CH3 CH CH3 CH CH3 Br H2O CH3 C CH3 CH2 CH3 OH 93% The mechanism is shown below. Here we see a hydride shift, since this converts the secondary carbocation into the tertiary. Migration of a methyl group does not occur since this would not result in a lower energy carbocation (i.e. secondary to secondary). docsity.com 12 CH3 CH CH3 CH CH3 Br CH3 C CH3 H C CH3 O H H fast CH3 C C CH3 H H CH3 H secondary carbocation tertiary carbocation CH3 C CH3 H C CH3 H O HH H2O CH3 C CH3 H C CH3 H O H H OH CH3 C C CH3 H CH3 H O HH minor (7%) CH3 C C CH3 H CH3 H O H major (93%) Solvents Effects SN1 Reactions: The solvent can have a large effect on the rate of the substitution reaction. In general, the rate of a SN1 reaction increases dramatically with increasing solvent polarity. For the following reaction, look at the increase in rate as the solvent polarity increases. CH3 C CH3 CH3 Cl + HO Solvent CH3 C CH3 CH3 O Solvent Solvent CH3 C O OH Polarity Rate 6 1 CH3 OH 33 4 H C O OH 58 5 x 10 3 acetic acid methanol formic acid H O H water 78 5 x 10 5 A polar protic solvent helps to stabilize both the anion and cation that develop in the transition state and so lowers the energy of the transition states, thereby increasing the rate. docsity.com 15 CH3CH2 CH Cl CH H CH3 + Na+ I CH3CH2 CH CH H CH3 I + NaCl majorweak base, good nucleophile SN2 Other examples of species that are good nucleophiles but relatively weak bases and so give mainly SN2 reactions with secondary substrates are: I Br Cl RS HS N C R C O O N3 R3N With tertiary (3°) Substrates: Elimination reactions are favored with strong bases such as RO- and HO-. In solvolysis conditions and with weak bases, there is a combination of competing SN1 and E1 reactions. Substitution generally prevails over elimination but there is always a mixture of the two products. CH3 C CH3 Br CH2CH3 HOCH2CH3 25° C CH3 C CH3 OCH2CH3 CH2CH3 CH3 C CH3 CHCH3 64% + + CH3 C CH2 CH2CH3 36% weak base, weak nucleophile CH3 C CH3 Br CHCH3 NaOCH2CH3 HOCH2CH3 H CH3 C CH3 CHCH3 ~ 100% strong base, good nucleophile Increasing the reaction temperature will tend to favor elimination over substitution. In elimination reactions we are breaking two relatively strong sigma-bonds and forming one sigma-bond and a relatively weaker π−bond. In practical terms, if an elimination reaction is desired, use strong E2 conditions (high temperature and a hindered strong base). To favor a substitution reaction, use lower temperature, an unhindered nucleophile and an unhindered substrate. docsity.com 16 Sulfonate Esters Alkyl sulfonates esters are also very good leaving groups, similar in leaving group ability to halogens. They are prepared from alcohols by reaction with a sulfonyl chloride. A common sulfonyl chloride is p-toluene sulfonyl chloride. Generally a mild, non- nucleophilic base such as pyridine or triethyl amine is used to neutralize the HCl that is formed in the reaction. CH3CH2 O H + Cl S O O CH3 p-toluenesulfonyl chloride N CH3CH2 O S H O O Cl CH3 O S O O CH3CH3CH2 H + Cl N O S O O CH3CH3CH2 sulfonyl ester Ts = tosyl group N HCl + The sulfonyl ester can then be attacked by strongly basic nucleophiles to give substitution products with loss of the tosyl group. O S O O CH3CH3CH2CH3CH2 O Na + HOCH2CH3 CH3CH2 O CH2CH3 + O S O O CH3 The tosyl group is a very good leaving group, equivalent to a halogen, because it forms a resonance-stabilized anion that is a weak base. Remember, by definition, a good leaving group is a weak base. O S O O CH3 O S O O CH3 O S O CH3 O The (-) charge is spread out over all three oxygens and is thereby stabilized. docsity.com 17 Note that the overall effect of making the alcohol into the tosylates is to convert the OH group into a good leaving group under mild, non-acidic conditions. As we have learned, we can convert the OH group into a good leaving group by protonation but this restricts the nucleophiles we can use to those that are very weakly basic such as the halogens. CH2 OH H Br CH2 O H H Br CH2 Br + H2O The Br- is a very weak base and will not deprotonate the oxygen. If we tried to do this same type of reaction with a more basic nucleophile like CH3O-, we would simply deprotonate the hydroxyl group in an acid-base reaction rather than a substitution reaction. Recall that the fastest reactions are always the proton transfer reactions. CH2 OH H OSO3H CH2 O H H Na+ -OCH3 CH2 OH + HOCH3 So, if we first make the tosylates we can safely react it with the basic sodium methoxide and get an excellent yield of the substitution product. CH2 OH Cl S O O CH3 N CH2 OTs Na+ -OCH3 CH2 OCH3 Note that the stereochemistry of the C-O bond does not change when the tosylates is made but it does undergo inversion in the subsequent SN2 reaction. CH3CH2CH2 C CH3 H OH (R)-2-pentanol + Cl Ts pyridine CH3CH2CH2 C CH3 H OTs K+ C N C C CH3CH2CH2 CH3 H N (S)- configuration at chirality center. Configuration at chirality center is still (R). docsity.com